Triazolopyridine compounds

ABSTRACT

The invention relates to compounds of formula (I) and salts thereof: 
                         
wherein the substituents are as defined in the specification; a compound of formula (I) for use in the treatment of the human or animal body, in particular with regard to c-Met tyrosine kinase mediated diseases or conditions; the use of a compound of formula (I) for manufacturing a medicament for the treatment of such diseases; pharmaceutical compositions comprising a compound of the formula (I), optionally in the presence of a combination partner, and processes for the preparation of a compound of formula (I).

The invention relates to bicyclic compounds of formula (I) and saltsthereof, the uses of such compounds to treat the human or animal body,in particular with regard to a proliferative disease, pharmaceuticalcompositions comprising such compounds, combinations comprising acompound of formula (I), and processes for the preparation of suchcompounds.

INTRODUCTION

The Hepatocyte Growth Factor Receptor, herein referred to as c-Met, is areceptor tyrosine kinase that has been shown to be over-expressed and/orgenetically altered in a variety of malignancies, specifically, geneamplification and a number of c-Met mutations are found in various solidtumors, see e.g. WO 2007/126799. Further, the receptor tyrosine kinasec-Met is involved in the processes of migration, invasion andmorphogenesis that accompany embryogenesis and tissue regeneration.C-Met is also involved in the process of metastasis. Several lines ofevidence have indicated that c-Met plays a role in tumor pathogenesis.Gain of function germ line mutations in c-Met is associated withdevelopment of hereditary papillary renal cell carcinoma (PRCC).Amplification or mutations in c-Met have also been reported in sporadicforms of PRCC, in head and neck squamous cell carcinoma, in gastriccarcinoma, in pancreatic carcinoma and in lung cancer. Such alterationshave been shown in selected instances to confer dependence of the tumoron c-Met and/or resistance to other targeted therapies. Elevated levelsof c-Met, together with its unique ligand HGF/SF, are observed at highfrequency in multiple clinically relevant tumors. A correlation betweenincreased expression and disease progression, metastases and patientmortality has been reported in several cancers, including bladder,breast, squamous cell carcinoma and gastric carcinoma as well asleiomyosarcoma and glioblastoma.

c-Met inhibitors have been described in the prior art. For example, WO2008/008539, WO 2009/091374, WO 2010/019899 and WO 2010/007316 disclosecertain triazolopyridine derivatives which are useful in the treatmentof c-Met related diseases. WO 2008/051808, WO 2010/019899, WO2010/007316, WO 2009/056692, WO 2010/089506, WO 2010/089507, WO2010/089508, and WO 2010/089509 disclose a variety of fused heterocycliccompounds with different kinds of 9-10 membered heteroaryl moietieslinked via an S— linker, which compounds are indicated for the treatmentof c-Met mediated diseases. Furthermore, international patentapplications WO 2011/018454 and WO 2011/020861 disclose certainsubstituted triazolopyridazine derivatives with an oxime or hydrazonemoiety linked to a potentially substituted quinoline moiety which areuseful in the treatment of c-Met mediated disorders.

SUMMARY OF THE INVENTION

It is an aim of the present invention to provide further compounds thatmodulate, and in particular inhibit, c-Met. It has now been found thatthe compounds of the formula (I) described herein are inhibitors ofc-Met and have a number of therapeutic applications. For example, thecompounds of formula (I) are suitable for use in the treatment ofdiseases dependent on c-Met activity, especially solid tumors ormetastasis derived therefrom. Through the inhibition of c-Met, compoundsof the invention also have utility as anti-inflammatory agents, forexample for the treatment of an inflammatory condition which is due toan infection.

Preferably, the compounds of the invention are metabolically stable, arenon-toxic and demonstrate few side-effects. In addition, preferredcompounds of the invention exist in a physical form that is stable,non-hygroscopic and easily formulated. One aspect of the invention isdirected to compounds of formula (I) having an activity that is at leastsimilar, better superior to the activity of compounds of the prior art,or other similar compounds. Another aspect of the invention is directedto compounds of formula (I) having a good kinase selectivity. Inparticular, preferred compounds should have high affinity to the c-Metreceptor and show functional antagonistic activity, while having littleaffinity for other kinase receptors or for targets known to beassociated with adverse effects. In one aspect of the invention,preferred compounds demonstrate comparably low antagonistic activityagainst human PDE3 than related derivatives. Furthermore, the compoundsof the invention are metabolically stable, in particular with regard todegradation by aldehyde oxidase enzymatic activities. Preferredcompounds of the invention posses favourable pharmacokinetic properties,such as good in-vivo exposure and/or solubility and especially goodmetabolic stability, and/or do not form metabolites with unfavourablepharmacological properties. Particularly preferred compounds of theinvention have favourable characteristics in more than one of the assaysdescribed herein.

The present invention relates to a compound of the formula (I)

whereinR¹ is selected from:

-   (i) pyrazolyl, optionally substituted by (C₁-C₄)alkyl, said    (C₁-C₄)alkyl being optionally substituted by one OH group, and-   (ii) —CR⁹═N—O—R¹⁰, wherein    -   R⁹ is hydrogen or (C₁-C₄)alkyl; and,    -   R¹⁰ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being        optionally substituted by one OH group;        R² is selected from hydrogen and halo; and        R³ is selected from-   (i) optionally substituted —(C₀-C₂)alkyl-heterocyclyl¹, and-   (ii) —NHR⁴, wherein    -   R⁴ is selected from hydrogen, optionally substituted        —(C₀-C₂)alkyl-heterocyclyl³ and (C₁-C₄)alkyl, said (C₁-C₄)alkyl        being optionally substituted by one, two or three substituents        independently selected from OH and halo;        or a pharmaceutically acceptable salt thereof.

The present invention relates to a compound of the formula (I),

whereinR¹ is selected from:

-   (i) pyrazolyl, optionally substituted by (C₁-C₄)alkyl, said    (C₁-C₄)alkyl being optionally substituted by one OH group, and-   (ii) —CR⁹═N—O—R¹⁰, wherein    -   R⁹ is hydrogen or (C₁-C₄)alkyl; and,    -   R¹⁰ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being        optionally substituted by one OH group;        R² is selected from hydrogen and halo; and        R³ is optionally substituted —(C₀-C₂)alkyl-heterocyclyl¹,        wherein heterocyclyl¹ has the meaning as defined herein,        or a pharmaceutically acceptable salt thereof.

The present invention in particular relates to a compound of formula (I)

whereinR¹ is selected from

-   (i) pyrazolyl, optionally substituted by (C₁-C₄)alkyl, said    (C₁-C₄)alkyl being optionally substituted by one OH group, and-   (ii) —CR⁹═N—O—R¹⁰, wherein    -   R⁹ is hydrogen or (C₁-C₄)alkyl; and,    -   R¹⁰ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being        optionally substituted by one OH group;        R² is selected from hydrogen and halo; and        R³ is —(C₀-C₂)alkyl-heterocyclyl¹,        wherein heterocyclyl¹ is a 4, 5, 6, 7 or 8 membered saturated or        partially unsaturated N-heterocyclic ring which is attached via        the N-atom and optionally comprises additional 1 or 2 ring        heteroatoms independently selected from N, O and S in a position        or positions other than adjacent to the linking N atom, wherein        the total number of ring S-atoms does not exceed 1, and the        total number of ring O-atoms does not exceed 1,        wherein the N-heterocyclic ring is optionally substituted-   (i) by one, two or three substituents independently selected from    —OH, halo, —CONH₂, —CONH(C₁-C₄)alkyl, —CON((C₁-C₄)alkyl)₂,    —COO(C₁-C₄)alkyl, —NH₂, —NH—COO(C₁-C₄)alkyl, —NH(C₁-C₃)alkyl,    —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl¹,    —(C₃-C₈)cycloalkyl, phenyl and (C₁-C₄)alkyl, said (C₁-C₄)alkyl being    optionally substituted by one, two or three substituents    independently selected from OH and halo; wherein heterocyclyl¹ is a    5 or 6-membered saturated or partially unsaturated monocyclic group    comprising 1 or 2 ring heteroatoms independently selected from N and    O, wherein the total number of ring O atoms does not exceed 1, and    which is optionally substituted by one or two substituents    independently selected from OH and (C₁-C₄)alkyl; or-   (ii) by two groups which are attached to the same carbon atom and    are combined into a cyclic 4, 5, 6, or 7 membered saturated or    partially unsaturated ring system optionally comprising 1 or 2 ring    heteroatoms independently selected from N, O and S, wherein the    total number of ring S atoms does not exceed 1, which cyclic ring    system is optionally substituted by —OH or (C₁-C₄)alkyl;    and wherein the substituted N-heterocyclic ring is optionally    substituted by one or two additional (C₁-C₄)alkyl groups;    or a pharmaceutically acceptable salt thereof.

In one embodiment, R³ is selected from

-   (i) optionally substituted —(C₁-C₂)alkyl-heterocyclyl¹, under the    proviso that R¹ is optionally substituted pyrazole, and-   (ii) optionally substituted heterocyclyl¹, wherein heterocyclyl¹ has    the meaning as defined herein.

The meaning of “optionally substituted —(C₁-C₂)alkyl-heterocyclyl¹,under the proviso that R¹ is optionally substituted pyrazole” isequivalent to “optionally substituted —(C₁-C₂)alkyl-heterocyclyl¹,wherein R¹ is optionally substituted pyrazole”.

In one embodiment, the present invention relates to a compound of theformula (I), wherein

R¹ is selected from:

-   (i) pyrazolyl, optionally substituted by (C₁-C₄)alkyl, said    (C₁-C₄)alkyl being optionally substituted by one OH group, and-   (ii) —CR⁹═N—O—R¹⁰, wherein    -   R⁹ is hydrogen or (C₁-C₄)alkyl; and,    -   R¹⁰ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being        optionally substituted by one OH group;        R² is selected from hydrogen and halo; and        R³ is selected from-   (i) optionally substituted —(C₁-C₂)alkyl-heterocyclyl¹, under the    proviso that R¹ is optionally substituted pyrazole, and-   (ii) optionally substituted heterocyclyl¹,    wherein heterocyclyl¹ has the meaning as defined herein.

In one embodiment, the present invention relates to a compound of theformula (I), wherein

R¹ is pyrazolyl, optionally substituted by (C₁-C₄)alkyl, said(C₁-C₄)alkyl being optionally substituted by one OH group;

R² is selected from hydrogen and halo; and

R³ is optionally substituted —(C₀-C₂)alkyl-heterocyclyl¹, whereinheterocyclyl¹ has the meaning as defined herein,

or a pharmaceutically acceptable salt or solvate thereof.

In an alternative embodiment, the present invention relates to acompound of the formula (I), wherein

R¹ is —CR⁹═N—O—R¹⁰, wherein

-   -   R⁹ is hydrogen or (C₁-C₄)alkyl; and,    -   R¹⁰ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being        optionally substituted by one OH group;        R² is selected from hydrogen and halo; and        R³ is optionally substituted-heterocyclyl¹, wherein        heterocyclyl¹ has the meaning as defined herein,        or a pharmaceutically acceptable salt or solvate thereof.

One embodiment of the present invention relates to a compound of formula(I), wherein

R¹ is selected from 1-methyl-1H-pyrazol-4-yl, 1-yl-ethanone oxime, and1-yl ethanone O-(2-hydroxyethyl)-oxime, preferably R¹ is1-methyl-1H-pyrazol-4-yl,

R² is hydrogen or fluoro, and

R³ is optionally substituted heterocyclyl¹, wherein heterocyclyl¹ hasthe meaning as defined herein,

or a pharmaceutically acceptable salt or solvate thereof.

In an alternative embodiment, the present invention relates to acompound of the formula (I), wherein

R¹ is pyrazolyl, optionally substituted by (C₁-C₄)alkyl, said(C₁-C₄)alkyl being optionally substituted by one OH group;

R² is selected from hydrogen and halo; and

R³ is —NHR⁴, wherein R⁴ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkylbeing optionally substituted by one, two or three substituentsindependently selected from OH and halo;

or a pharmaceutically acceptable salt or solvate thereof.

In an alternative embodiment, the present invention relates to acompound of the formula (I), wherein

R¹ is selected from:

-   (i) pyrazolyl, optionally substituted by (C₁-C₄)alkyl, said    (C₁-C₄)alkyl being optionally substituted by one OH group, and-   (ii) —CR⁹═N—O—R¹⁰, wherein    -   R⁹ is hydrogen or (C₁-C₄)alkyl; and,    -   R¹⁰ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being        optionally substituted by one OH group;        R² is selected from hydrogen and halo; and        R³ is —NHR⁴, wherein R⁴ is optionally substituted        —(C₀-C₂)alkyl-heterocyclyl³; wherein heterocyclyl³ has the        meaning as defined herein,        or a pharmaceutically acceptable salt or solvate thereof.

DEFINITIONS

The following general definitions shall apply in this specification,unless otherwise specified:

Unless specified otherwise, the term “compound of the invention”, or“compounds of the invention”, or “a compound of the present invention”or “compounds of the present invention” refer to compounds of Formula(I) and subformulae thereof, prodrugs thereof, salts of the compoundsand/or prodrugs, hydrates or solvates of the compounds, salts and/orprodrugs, as well as all stereoisomers (including diastereoisomers andenantiomers), tautomers and isotopically labeled compounds (includingdeuterium substitutions), as well as inherently formed moieties (e.g.,polymorphs, solvates and/or hydrates).

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

Where the plural form (e.g. compounds, salts) is used, this includes thesingular (e.g. a single compound, a single salt). “A compound” does notexclude that (e.g. in a pharmaceutical formulation) more than onecompound of the formula (I) (or a salt thereof) is present.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

As used herein, the term “halo” means fluoro, chloro, bromo or iodo. Ina particular embodiment of the invention, halo is fluoro or chloro.Preferably, halo is fluoro.

As used herein, the term “heteroatoms” refers to nitrogen (N), oxygen(O) or sulfur (S) atoms, in particular nitrogen or oxygen.

Any non-cyclic carbon containing group or moiety with more than 1 carbonatom can be straight-chain or branched.

As used herein, the term “alkyl” refers to a straight-chain orbranched-chain alkyl group. For example, (C₁-C₄)alkyl includes methyl,ethyl, n- or iso-propyl, and n-, iso-, sec- or tert-butyl.

As used herein, the term “cycloalkyl” refers to a saturated or partiallyunsaturated monocyclic hydrocarbon groups having 3, 4, 5, 6, 7 or 8 ringcarbon atoms, preferably from 3 up to and including 6 ring carbon atoms.Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

In the context of R³ herein “optionally substituted—(C₀-C₂)alkyl-heterocyclyl¹” means the substitution is present on theheterocyclyl¹ of —(C₀-C₂)alkyl-heterocyclyl¹.

As used herein, the term “heterocyclyl¹” used as “heterocyclyl¹” aloneas well as a part of “—(C₀-C₂)alkyl-heterocyclyl¹” or“—(C₁-C₂)alkyl-heterocyclyl¹” or “-methyl-heterocyclyl¹” refers to a 4,5, 6, 7 or 8 membered saturated or partially unsaturated N-heterocyclicring which is attached via the N-atom and optionally comprisesadditional 1 or 2 ring heteroatoms independently selected from N, O andS in a position or positions other than adjacent to the linking N atom,wherein the total number of ring S-atoms does not exceed 1, and thetotal number of ring O-atoms does not exceed 1. Specific examples ofheterocyclyl¹ include, but are not limited to azetidinyl, pyrrolidinyl,2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-pyrrolyl, imidazolidinyl,4,5-dihydro-1H-imidazolyl, 2,5-dihydro-1H-imidazolyl,2,3-dihydro-1H-imidazolyl, 1,2-dihydropyridinyl,1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, morpholinyl,thiomorpholinyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolidinyl,2,3-dihydrooxazolyl, thiazolidinyl, 2,3-dihydrothiazolyl,hexahydropyrimidinyl, 1,2,5,6-tetrahydropyrimidinyl,1,4,5,6-tetrahydropyrimidinyl, 1,2,3,4-tetrahydropyrazinyl,1,2,3,6-tetrahydropyrazinyl, [1,3,5]triazinanyl, [1,3]oxazinanyl,3,4-dihydro-2H-[1,4]oxazinyl, 3,4-dihydro-2H-[1,3]oxazinyl,3,6-dihydro-2H-[1,3]oxazinyl, [1,3]thiazinanyl,3,6-dihydro-2H-[1,3]thiazinyl, 3,4-dihydro-2H-[1,3]thiazinyl,3,4-dihydro-2H-[1,4]thiazinyl, azepanyl, diazepanyl, oxazepanyl, andthiazepanyl.

In one embodiment, the term “heterocyclyl¹” refers to a 4, 5, 6, or 7membered saturated N-heterocyclic ring which is attached via the N-atomand optionally comprises one additional ring heteroatom independentlyselected from N and O in a position other than adjacent to the linking Natom. Specific examples of such heterocyclyl¹ include, but are notlimited to azetidinyl, pyrrolidinyl, 2,3-dihydro-1H-pyrrolyl,2,5-dihydro-1H-pyrrolyl, imidazolidinyl, 4,5-dihydro-1H-imidazolyl,2,5-dihydro-1H-imidazolyl, 2,3-dihydro-1H-imidazolyl,1,2-dihydropyridinyl, 1,2,3,4-tetrahydropyridinyl,1,2,3,6-tetrahydropyridinyl, morpholinyl, piperidinyl, piperazinyl,quinuclidinyl, oxazolidinyl, 2,3-dihydrooxazolyl,2,3-hexahydropyrimidinyl, 1,2,5,6-tetrahydropyrimidinyl,1,4,5,6-tetrahydropyrimidinyl, 1,2,3,4-tetrahydropyrazinyl,1,2,3,6-tetrahydropyrazinyl, [1,3]oxazinanyl,3,4-dihydro-2H-[1,4]oxazinyl, 3,4-dihydro-2H-[1,3]oxazinyl,3,6-dihydro-2H-[1,3]oxazinyl, azepanyl, diazepanyl, and oxazepanyl.Preferred examples of such heterocyclyl¹ include, but are not limited topiperidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl, morpholin-4-yl,azetidin-1-yl, and 1,4-diazepan-1-yl.

In another embodiment, the term “heterocyclyl¹” refers to a 5 or 6membered saturated N-heterocyclic ring which is attached via the N-atomand optionally comprises one additional ring heteroatoms independentlyselected from N and O in a position other than adjacent to the linking Natom. Preferred examples of such heterocyclyl¹ include, but are notlimited to piperidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl, andmorpholin-4-yl, preferably piperazin-1-yl and morpholin-4-yl.

Within the context of the present invention, a heterocyclyl¹ group ofthe present invention (being an N-heterocyclic ring as defined above)can be optionally substituted (i) by one, two or three substituentsindependently selected from —OH, halo, —CONH₂, —CONH(C₁-C₄)alkyl,—CON((C₁-C₄)alkyl)₂, —COO(C₁-C₄)alkyl, —NH₂, —NH—COO(C₁-C₄)alkyl,—NH(C₁-C₃)alkyl, —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl²,—(C₃-C₈)cycloalkyl, phenyl and (C₁-C₄)alkyl, said (C₁-C₄)alkyl beingoptionally substituted by one, two or three substituents independentlyselected from OH and halo; or (ii) by two groups which are attached tothe same carbon atom and are combined into a cyclic 4, 5, 6, or 7membered saturated or partially unsaturated ring system optionallycomprising 1 or 2 ring heteroatoms independently selected from N, O andS, wherein the total number of ring S atoms does not exceed 1, whichcyclic ring system is optionally substituted by —OH or (C₁-C₄)alkyl.Additionally, heterocyclyl¹ can be substituted with one or two further(C₁-C₄)alkyl groups.

In one embodiment, a heterocyclyl¹ group can be optionally substituted(i) by one, two or three substituents independently selected from —OH,halo, —COO(C₁-C₄)alkyl, —NH₂, —NH—COO(C₁-C₄)alkyl, —NH(C₁-C₃)alkyl,—N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl², —(C₃-C₈)cycloalkyl,phenyl and (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionally substitutedby one, two or three substituents independently selected from OH andhalo; or (ii) by two groups which are attached to the same carbon atomand are combined into a cyclic 4, 5, or 6 membered saturated ring systemoptionally comprising 1 ring heteroatom independently selected from Nand O.

In one embodiment of the present invention, a heterocyclyl¹ group asdefined above comprising an additional ring N-atom is substituted atsuch additional ring N-atom with a substituent selected from cyclohexyl,phenyl and (C₁-C₄)alkyl, preferably a (C₁-C₂)alkyl group, optionallysubstituted by one, two or three substituents independently selectedfrom OH and halo.

In a further embodiment, a heterocyclyl¹ group as defined above can beoptionally substituted

-   (i) at one or two ring C-atoms by overall one or two substituents    independently selected from —OH, halo, —NH₂, —NH—COO(C₁-C₄)alkyl,    —NH(C₁-C₃)alkyl, —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl²,    and (C₁-C₄)alkyl;-   (ii) at the optionally present additional ring N-atom by one    substituent selected from —COO(C₁-C₄)alkyl, —(C₅-C₆)cycloalkyl,    phenyl and (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionally    substituted by one, two or three substituents independently selected    from OH and halo; or-   (iii) by two groups which are attached to the same carbon atom and    are combined into a cyclic 4, 5, or 6 membered saturated ring system    comprising 1 ring O-atom.

In another embodiment, a heterocyclyl¹ group as defined above can beoptionally substituted

-   (i) at one or two ring C-atoms by overall one or two substituents    independently selected from —OH, halo, —NH₂, —NH(C₁-C₃)alkyl,    —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl², and (C₁-C₄)alkyl;-   (ii) at the optionally present additional ring N-atom by one    substituent selected from —(C₅-C₆)cycloalkyl, phenyl and    (C₁-C₂)alkyl, said (C₁-C₂)alkyl being optionally substituted by one,    two or three substituents independently selected from OH and halo;    or-   (iii) by two groups which are attached to the same carbon atom and    are combined into a cyclic 4 or 6 membered saturated ring system    comprising 1 ring O-atom.

In a further embodiment, a heterocyclyl¹ group as defined above can beoptionally substituted

-   (i) at one or two ring C-atoms by overall one or two substituents    independently selected from —OH, halo, —NH₂, —N(methyl)₂, —O-methyl,    heterocyclyl², and methyl;-   (ii) at the optionally present additional ring N-atom by one    substituent selected from cyclohexyl, phenyl and methyl; or-   (iii) by two groups which are attached to the same carbon atom and    are combined into a cyclic 4 or 6 membered saturated ring system    comprising 1 ring O-atom.

In another preferred embodiment, a heterocyclyl¹ group as defined abovecan be optionally substituted

-   (i) at one or two ring C-atoms by overall one or two substituents    independently selected from —OH, halo, —NH₂, —N(methyl)₂, —O-methyl,    piperidin-1-yl, pyrrolidin-1-yl, and methyl;-   (ii) at the optionally present additional ring N-atom by one    substituent selected from cyclohexyl and methyl; or-   (iii) by two groups which are attached to the same carbon atom and    are combined into a cyclic 4 or 6 membered saturated ring system    comprising 1 ring O-atom.

In one embodiment of the present invention, the term “optionallysubstituted heterocyclyl¹” refers to a group selected frompiperidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl, morpholin-4-yl,azetidin-1-yl, 1,4-diazepan-1-yl, 3-aminopyrrolidin-1-yl,3-N,N-dimethylaminopyrrolidin-1-yl, 3-aminopiperidin-1-yl,4-aminopiperidin-1-yl, 4-(pyrrolidin-1-yl)piperidin-1-yl,1,4′-bipiperidin-1′-yl, 4-methoxypiperidin-1-yl,4-hydroxypiperidin-1-yl, 4,4-difluoro-piperidin-1-yl,2,2,2-trifluoroethylpiperazin-1-yl, 4-cyclohexylpiperazin-1-yl,4-phenylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl,2-methylpiperazin-1-yl, 4-methylpiperazin-1-yl, 2-methylmorpholin-4-yl,2,6-dimethylmorpholin-4-yl, 3-methylmorpholin-4-yl,4-methyl-1,4-diazepan-1-yl, 4-(2-hydroxyethyl)-1,4-diazepan-1-yl,2-oxa-6-azaspiro[3.3]heptan-6-yl, and 8-oxa-2-azaspiro[4.5]decan-2-yl.Preferably, optionally substituted “heterocyclyl¹” refers to a groupselected from piperazin-1-yl, morpholin-4-yl, 4-methoxypiperidin-1-yl,4-hydroxypiperidin-1-yl, 3,5-dimethylpiperazin-1-yl,3-N,N-dimethylaminopyrrolidin-1-yl, 3-amino-piperidin-1-yl,3-amino-pyrrolidin-1-yl and 4-methyl-piperazin-1-yl.

In another embodiment of the present invention, the term “heterocyclyl¹”refers to

-   a) a 4, 5 or 6 membered saturated N-heterocyclic ring attached via    the N-atom and substituted    -   (i) at one or two ring C-atoms by overall one or two        substituents selected from —OH, fluoro, —N(methyl)₂, methoxy,        pyrrolidin-1-yl, and methyl; or    -   (ii) by two groups which are attached to the same carbon atom        and are combined into a cyclic 4 or 6 membered saturated ring        system comprising 1 ring O-atom;-   b) a 6 membered saturated N-heterocyclic ring attached via the    N-atom and comprising one additional ring O-atom in a position other    than adjacent to the linking N atom, wherein the N-heterocyclic ring    is optionally substituted by one or two methyl groups; or-   c) a 6 or 7 membered saturated N-heterocyclic ring attached via the    N-atom and comprising one additional ring N-atom in a position other    than adjacent to the linking N atom, wherein the N-heterocyclic ring    is optionally substituted    -   (i) at the additional ring N-atom with a substituent selected        from cyclohexyl, phenyl and (C₁-C₂)alkyl, said (C₁-C₂)alkyl        being optionally substituted by one, two or three substituents        independently selected from OH and halo; or    -   (ii) at one or two ring C-atoms adjacent to the additional ring        N-atom by one or two methyl groups.

In a further preferred embodiment of the present invention, the term“heterocyclyl¹” refers to

-   a) a 4, 5 or 6 membered saturated N-heterocyclic ring attached via    the N-atom and substituted    -   (i) at one ring C-atom by —OH, difluoro, —N(methyl)₂, methoxy,        piperidin-1-yl, or pyrrolidin-1-yl; or    -   (ii) by two groups which are attached to the same carbon atom        and are combined into a cyclic 4 or 6 membered saturated ring        system comprising 1 ring O-atom;-   b) a 6 membered saturated N-heterocyclic ring attached via the    N-atom and comprising one additional ring O-atom in a position other    than adjacent to the linking N atom, wherein the N-heterocyclic ring    is optionally substituted by one or two methyl groups; or-   c) a 6 or 7 membered saturated N-heterocyclic ring attached via the    N-atom and comprising one additional ring N-atom in a position other    than adjacent to the linking N atom, wherein the N-heterocyclic ring    is substituted    -   (i) at the additional ring N-atom with a methyl group; or    -   (ii) at one or two ring C-atoms adjacent to the additional ring        N-atom by one or two methyl groups.

Preferably, the term “heterocyclyl¹” refers to a group selected frompiperazin-1-yl, morpholin-4-yl, 4-methoxypiperidin-1-yl,4-hydroxypiperidin-1-yl, 3,5-dimethylpiperazin-1-yl,3-N,N-dimethylaminopyrrolidin-1-yl, and 4-methyl-piperazin-1-yl; inparticular piperazin-1-yl, morpholin-4-yl, 4-methoxypiperidin-1-yl,4-hydroxypiperidin-1-yl, 3,5-dimethylpiperazin-1-yl, and4-methyl-piperazin-1-yl.

As used herein, the term “heterocyclyl²” refers to a 5 or 6-memberedsaturated or partially unsaturated monocyclic group comprising 1 or 2ring heteroatoms independently selected from N and O, wherein the totalnumber of ring O atoms does not exceed 1, and which is optionallysubstituted by one or two substituents independently selected from OHand (C₁-C₄)alkyl.

In one embodiment, “heterocyclyl²” refers to a 5 or 6-membered saturatedmonocyclic group comprising 1 ring heteroatom independently selectedfrom N and O.

In another preferred embodiment, wherein “heterocyclyl²” refers to a 5or 6-membered saturated N-heterocyclic ring which is attached via theN-atom.

Specific examples of heterocyclyl² include, but are not limited to,tetrahydrofuranyl, tetrahydrothiophenyl, 3,6-dihydro-2H-pyridinyl,1,2,3,4-tetrahydropyridinyl, 1,2,5,6-tetrahydropyridinyl, pyrrolidinyl,morpholinyl, piperidinyl, piperazinyl, oxazolinyl, oxazolidinyl,3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl,tetrahydropyranyl, and dihydro-1H-pyrrolyl. In one embodiment,heterocyclyl² includes piperidinyl and pyrrolidinyl, in particularpiperidin-1-yl and pyrrolidin-1-yl. Heterocyclyl² is optionallysubstituted by —OH or (C₁-C₃)alkyl, preferably methyl. In a preferredembodiment, heterocyclyl² is not substituted.

As used herein, the term “heterocyclyl³” refers to a 4, 5, 6, 7 or8-membered saturated or partially unsaturated heterocyclic ring which isattached via a ring C-atom and comprises 1 ring heteroatom selected fromN, O and S in a position other than adjacent to the linking C atom.Specific examples of such heterocyclyl³ include, but are not limited toazetidinyl, oxetanyl, pyrrolidinyl, 2,3-dihydro-1H-pyrrolyl,2,5-dihydro-1H-pyrrolyl, tetrahydrofuryl, tetrahydrothiophenyl,piperidinyl, 1,2-dihydropyridinyl, 3,6-dihydro-2H-pyridinyl,1,2,3,4-tetrahydropyridinyl, 1,2,3,6-tetrahydropyridinyl, quinuclidinyl,tetrahydropyranyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl,tetrahydrothiopyranyl, oxepanyl and azepanyl.

In one embodiment, the term “heterocyclyl³” refers to a 4, 5, 6 or7-membered saturated heterocyclic ring which is attached via a ringC-atom and comprises 1 ring heteroatom selected from N and O in aposition other than adjacent to the linking C atom. Specific examples ofsuch heterocyclyl¹ include, but are not limited to azetidinyl, oxetanyl,pyrrolidinyl, tetrahydrofuryl, piperidinyl, tetrahydropyranyl, oxepanyland azepanyl. Preferred examples of such heterocyclyl³ include, but arenot limited to oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl, andtetrahydropyranyl; in particular oxetan-3-yl, pyrrolidin-3-yl,tetrahydrofuran-3-yl, piperidin-4-yl, and tetrahydropyran-4-yl.

Within the context of the present invention, a heterocyclyl³ group ofthe present invention (being an heterocyclic ring attached via a ringC-atom as defined above) can be optionally substituted by one or twosubstituents independently selected from —OH, halo, —COO(C₁-C₄)alkyl,—O(C₁-C₄)alkyl, and (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionallysubstituted by one, two or three substituents independently selectedfrom OH and halo. Additionally, heterocyclyl³ can be substituted by oneor two further (C₁-C₄)alkyl groups.

In one embodiment of the present invention, a heterocyclyl³ group asdefined above comprising a ring N-atom is substituted

-   -   (i) at such ring N-atom with a substituent selected from        —COO(C₁-C₄)alkyl and (C₁-C₄)alkyl, preferably a (C₁-C₂)alkyl        group, optionally substituted by one, two or three substituents        independently selected from OH and halo, or    -   (ii) at one or both ring C-atoms next to the ring N-atom by up        to four (C₁-C₂)alkyl groups.

In one embodiment of the present invention, the term “optionallysubstituted heterocyclyl³” refers to a group selected from oxetan-3-yl,pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, tetrahydrofuran-3-yl,piperidin-4-yl, 2,2,6,6-tetramethylpiperidin-4-yl,1-methyl-piperidin-4-yl, and tetrahydropyran-4-yl. Preferably,“optionally substituted heterocyclyl³” refers to a group selected fromoxetan-3-yl, 1-methyl-pyrrolidin-3-yl, tetrahydro-furan-3-yl,2,2,6,6-tetramethylpiperidin-4-yl, 1-methyl-piperidin-4-yl, andtetrahydropyran-4-yl.

EMBODIMENTS

In one embodiment, the invention provides a compound of formula (I) or asalt or solvate thereof, wherein R¹ is pyrazolyl, optionally substitutedby (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionally substituted by oneOH group. In particular, R¹ is 1H-pyrazol-4-yl, optionally substitutedby methyl or 2-hydroxy-ethyl. In a preferred embodiment of theinvention, R¹ is selected from 1-methyl-1H-pyrazol-4-yl,1H-pyrazol-4-yl, and 1-(2-hydroxy-ethyl)-1H-pyrazol-4-yl. In particular,R¹ is 1-methyl-1H-pyrazol-4-yl.

In an alternative embodiment, the invention provides a compound offormula (I) or a salt or solvate thereof, wherein R¹ is —CR⁹═N—O—R¹⁰,wherein R⁹ is hydrogen or (C₁-C₄)alkyl; and R¹⁰ is hydrogen or(C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionally substituted by one OHgroup. In one embodiment, R¹ is —CR⁹═N—O—R¹⁰, wherein R⁹ is(C₁-C₂)alkyl; and, R¹⁰ is hydrogen or (C₁-C₂)alkyl, said (C₁-C₂)alkylbeing optionally substituted by one OH group. In a preferred embodimentof the invention, R¹ is —CR⁹═N—O—R¹⁰, wherein R⁹ is methyl; and R¹⁰ ishydrogen or 2-hydroxy-ethyl. In particular, R¹ is selected from1-yl-ethanone oxime and 1-yl ethanone O-(2-hydroxy-ethyl)-oxime.Preferably, when R¹ is —CR⁹═N—O—R¹⁰, then R³ is optionally substitutedheterocyclyl¹ as defined herein.

In one embodiment, the invention provides a compound of formula (I) or asalt or solvate thereof, wherein R² is selected from hydrogen andfluoro. In one embodiment, R² is hydrogen. In another embodiment, R² isfluoro. Preferably, R² is hydrogen.

In another embodiment, the invention provides a compound of formula (I)or a salt or solvate thereof, wherein R³ is —(C₀-C₁)alkyl-heterocyclyl¹.In another embodiment, R³ is —CH₂-heterocyclyl¹. In another preferredembodiment, R³ is heterocyclyl¹. The heterocyclyl¹ group has a meaningand can be optionally substituted as defined herein.

In a preferred embodiment of the invention, R³ is —CH₂-heterocyclyl¹ orheterocyclyl¹, wherein heterocyclyl¹ is a 4, 5, 6, or 7 memberedsaturated N-heterocyclic ring which is attached via the N-atom andoptionally comprises one additional ring heteroatom independentlyselected from N and O in a position other than adjacent to the linking Natom, wherein the N-heterocyclic ring is optionally substituted

-   (i) by one, two or three substituents independently selected from    —OH, halo, —COO(C₁-C₄)alkyl, —NH₂, —NH—COO(C₁-C₄)alkyl,    —NH(C₁-C₃)alkyl, —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl²,    —(C₃-C₈)cycloalkyl, phenyl and (C₁-C₄)alkyl, said (C₁-C₄)alkyl being    optionally substituted by one, two or three substituents    independently selected from OH and halo;    -   wherein heterocyclyl¹ is a 5 or 6-membered saturated monocyclic        group comprising 1 ring heteroatom independently selected from N        and O; or-   (ii) by two groups which are attached to the same carbon atom and    are combined into a cyclic 4, 5, or 6 membered saturated ring system    optionally comprising 1 ring heteroatom independently selected from    N and O

In another embodiment of the invention, R³ is —CH₂-heterocyclyl¹,wherein heterocyclyl¹ is a 5 or 6 membered saturated N-heterocyclic ringwhich is attached via the N-atom and optionally comprises one additionalring heteroatom selected from N and O in a position other than adjacentto the linking N atom, wherein any additional ring N-atom is substitutedwith an (C₁-C₄)alkyl group. Preferably, R³ is4-methyl-piperazin-1-ylmethyl or morpholin-4-ylmethyl. In embodimentswhen R³ is such —CH₂-heterocyclyl¹, then R¹ is preferably optionallysubstituted pyrazole.

In a preferred embodiment of the invention, R³ is heterocyclyl¹ being a4, 5, 6, or 7 membered saturated N-heterocyclic ring which is attachedvia the N-atom and optionally comprises one additional ring heteroatomindependently selected from N and O in a position other than adjacent tothe linking N atom, wherein the N-heterocyclic ring is optionallysubstituted

-   (i) at one or two ring C-atoms by overall one or two substituents    independently selected from —OH, halo, —NH₂, —NH—COO(C₁-C₄)alkyl,    —NH(C₁-C₃)alkyl, —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl²,    and (C₁-C₄)alkyl;    -   preferably selected from —OH, halo, —NH₂, —NH(C₁-C₃)alkyl,        —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl², and        (C₁-C₄)alkyl,    -   more preferably from —OH, halo, —N(methyl)₂, —O-methyl,        heterocyclyl², and methyl;    -   wherein heterocyclyl² is a 5 or 6-membered saturated        N-heterocyclic ring which is attached via the N-atom;-   (ii) at the optionally present additional ring N-atom by one    substituent selected from —COO(C₁-C₄)alkyl, —(C₅-C₆)cycloalkyl,    phenyl and (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionally    substituted by one, two or three substituents independently selected    from OH and halo;    -   preferably selected from —(C₅-C₆)cycloalkyl, phenyl and        (C₁-C₂)alkyl, said (C₁-C₂)alkyl being optionally substituted by        one, two or three substituents independently selected from OH        and halo;    -   more preferably by one substituent selected from cyclohexyl,        phenyl and methyl; or-   (iii) by two groups which are attached to the same carbon atom and    are combined into a cyclic 4, 5, or 6 membered saturated ring system    comprising 1 ring O-atom, preferably by two groups which are    attached to the same carbon atom and are combined into a cyclic 4 or    6 membered saturated ring system comprising 1 ring O-atom.

In a preferred embodiment of the invention, R³ is heterocyclyl¹ being a4, 5, 6, or 7 membered saturated N-heterocyclic ring which is attachedvia the N-atom and optionally comprises one additional ring heteroatomindependently selected from N and O in a position other than adjacent tothe linking N atom, wherein the N-heterocyclic ring is optionallysubstituted

-   (i) at one or two ring C-atoms by overall one or two substituents    independently selected from —OH, halo, —NH₂, —N(methyl)₂, —O-methyl,    heterocyclyl², and methyl;    -   wherein heterocyclyl² is a 5 or 6-membered saturated        N-heterocyclic ring which is attached via the N-atom;-   (ii) at the optionally present additional ring N-atom by one    substituent selected from cyclohexyl, phenyl and methyl; or-   (iii) by two groups which are attached to the same carbon atom and    are combined into a cyclic 4 or 6 membered saturated ring system    comprising 1 ring O-atom.

In a preferred embodiment of the invention, R³ is heterocyclyl¹ beingselected from piperidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl,morpholin-4-yl, azetidin-1-yl, and 1,4-diazepan-1-yl, whereinheterocyclyl¹ is optionally substituted

-   (i) at one or two ring C-atoms by overall one or two substituents    independently selected from —OH, halo, —NH₂, —N(methyl)₂, —O-methyl,    piperidin-1-yl, pyrrolidin-1-yl, and methyl;-   (ii) at the optionally present additional ring N-atom by one    substituent selected from cyclohexyl and methyl; or-   (iii) by two groups which are attached to the same carbon atom and    are combined into a cyclic 4 or 6 membered saturated ring system    comprising 1 ring O-atom.

In another embodiment, the invention provides a compound of formula (I)or a salt or solvate thereof, wherein R³ is heterocyclyl¹ being selectedfrom piperidin-1-yl, pyrrolidin-1-yl, piperazin-1-yl, morpholin-4-yl,azetidin-1-yl, and 1,4-diazepan-1-yl, 3-aminopyrrolidin-1-yl,3-N,N-dimethylaminopyrrolidin-1-yl, 3-aminopiperidin-1-yl,4-aminopiperidin-1-yl, 4-(pyrrolidin-1-yl)piperidin-1-yl,1,4′-bipiperidin-1′-yl, 4-methoxypiperidin-1-yl,4-hydroxypiperidin-1-yl, 4,4-difluoro-piperidin-1-yl,2,2,2-trifluoroethylpiperazin-1-yl, 4-cyclohexylpiperazin-1-yl,4-phenylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl,2-methylpiperazin-1-yl, 4-methyl-piperazin-1-yl, 2-methylmorpholin-4-yl,2,6-dimethylmorpholin-4-yl, 3-methylmorpholin-4-yl,4-methyl-1,4-diazepan-1-yl, 4-(2-hydroxyethyl)-1,4-diazepan-1-yl,2-oxa-6-azaspiro[3.3]heptan-6-yl, and 8-oxa-2-azaspiro[4.5]decan-2-yl.Preferably, R³ is heterocyclyl¹ being selected from4,4-difluoro-piperidin-1-yl, 3-N,N-dimethylaminopyrrolidin-1-yl,4-methoxypiperidin-1-yl, 1,4′-bipiperidin-1′-yl,4-(pyrrolidin-1-yl)piperidin-1-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl,4-hydroxypiperidin-1-yl, 8-oxa-2-azaspiro[4.5]decan-2-yl,3,5-dimethylpiperazin-1-yl, 4-methyl-piperazin-1-yl,4-methyl-1,4-diazepan-1-yl, piperazin-1-yl, morpholin-4-yl,2-methylmorpholin-4-yl, and 2,6-dimethylmorpholin-4-yl.

In particular, R³ is heterocyclyl¹ being selected from piperazin-1-yl,morpholin-4-yl, 4-methoxypiperidin-1-yl, 4-hydroxypiperidin-1-yl,3,5-dimethylpiperazin-1-yl, 3-N,N-dimethylaminopyrrolidin-1-yl,3-amino-piperidin-1-yl, 3-amino-pyrrolidin-1-yl and4-methyl-piperazin-1-yl. In a further embodiment thereof, R³ isheterocyclyl¹ being selected from piperazin-1-yl, morpholin-4-yl,4-methoxypiperidin-1-yl, 4-hydroxypiperidin-1-yl,3,5-dimethylpiperazin-1-yl, and 4-methyl-piperazin-1-yl.

In another embodiment, the invention provides a compound of formula (I)or a salt or solvate thereof, wherein

R¹ is selected from 1-methyl-1H-pyrazol-4-yl, 1-yl-ethanone oxime, and1-yl ethanone O-(2-hydroxyethyl)-oxime, preferably1-methyl-1H-pyrazol-4-yl,

R² is hydrogen or fluoro,

R³ is heterocyclyl¹, wherein heterocyclyl¹ is selected from

-   a) a 4, 5 or 6 membered saturated N-heterocyclic ring attached via    the N-atom and substituted    -   (i) at one or two ring C-atom or atoms by overall one or two        substituents selected from —OH, fluoro, —NH₂, —N(methyl)₂,        methoxy, piperidin-1-yl, pyrrolidin-1-yl, and methyl; or    -   (ii) by two groups which are attached to the same carbon atom        and are combined into a cyclic 4 or 6 membered saturated ring        system comprising 1 ring O-atom;-   b) a 6 membered saturated N-heterocyclic ring attached via the    N-atom and comprising one ring O-atom in a position other than    adjacent to the linking N atom, wherein the N-heterocyclic ring is    optionally substituted by one or two methyl groups; and-   c) a 6 or 7 membered saturated N-heterocyclic ring attached via the    N-atom and comprising one additional ring N-atom in a position other    than adjacent to the linking N atom, wherein the N-heterocyclic ring    is optionally substituted    -   (i) at the additional ring N-atom by a substituent selected from        cyclohexyl, phenyl and (C₁-C₂)alkyl, said (C₁-C₂)alkyl being        optionally substituted by one, two or three substituents        independently selected from OH and halo; or    -   (ii) at one or two ring C-atoms by one or two methyl groups.

In this embodiment, R³ is preferably heterocyclyl¹, whereinheterocyclyl¹ is selected from

-   a) a 4, 5 or 6 membered saturated N-heterocyclic ring attached via    the N-atom and substituted    -   (i) at one ring C-atom by —OH, difluoro, —NH₂, —N(methyl)₂,        methoxy, piperidin-1-yl, and pyrrolidin-1-yl; or    -   (ii) by two groups which are attached to the same carbon atom        and are combined into a cyclic 4 or 6 membered saturated ring        system comprising 1 ring O-atom;-   b) a 6 membered saturated N-heterocyclic ring attached via the    N-atom and comprising one ring O-atom in a position other than    adjacent to the linking N atom, wherein the N-heterocyclic ring is    optionally substituted by one or two methyl groups; and-   c) a 6 or 7 membered saturated N-heterocyclic ring attached via the    N-atom and comprising one additional ring N-atom in a position other    than adjacent to the linking N atom, wherein the N-heterocyclic ring    is optionally substituted    -   (i) at the additional ring N-atom by a substituent selected from        cyclohexyl and methyl; or    -   (ii) at one or two ring C-atoms adjacent to the additional ring        N-atom by one or two methyl groups.

In a preferred embodiment, the invention provides a compound of formula(I) or a pharmaceutically acceptable salt or solvate thereof, wherein

R¹ is selected from 1-methyl-1H-pyrazol-4-yl, 1-yl-ethanone oxime, and1-yl ethanone O-(2-hydroxyethyl)-oxime, preferably1-methyl-1H-pyrazol-4-yl,

R² is hydrogen or fluoro, and

R³ is heterocyclyl¹, wherein heterocyclyl¹ is selected frompiperazin-1-yl, morpholin-4-yl, 4-methoxypiperidin-1-yl,4-hydroxypiperidin-1-yl, 3,5-dimethylpiperazin-1-yl,3-N,N-dimethylaminopyrrolidin-1-yl, 3-amino-piperidin-1-yl,3-amino-pyrrolidin-1-yl and 4-methyl-piperazin-1-yl.

In another embodiment thereof, the invention provides a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof,wherein

R¹ is selected from 1-methyl-1H-pyrazol-4-yl,

R² is hydrogen or fluoro, and

R³ is heterocyclyl¹, wherein heterocyclyl¹ is selected frompiperazin-1-yl, morpholin-4-yl, 4-methoxypiperidin-1-yl,4-hydroxypiperidin-1-yl, 3,5-dimethylpiperazin-1-yl, and4-methyl-piperazin-1-yl.

In an alternative embodiment, the present invention relates to acompound of the formula (I), wherein

R¹ is selected from 1-methyl-1H-pyrazol-4-yl, 1-yl-ethanone oxime, and1-yl ethanone O-(2-hydroxyethyl)-oxime, preferably1-methyl-1H-pyrazol-4-yl;

R² is hydrogen or fluoro; and

R³ is —NHR⁴, wherein R⁴ is —(C₀-C₁)alkyl-heterocyclyl³; whereinheterocyclyl³ refers to a 4, 5 or 6-membered saturated heterocyclic ringwhich is attached via a ring C-atom and comprises 1 ring heteroatomselected from N and O in a position other than adjacent to the linking Catom, wherein a heterocyclyl³ group comprising a ring N-atom issubstituted

-   (i) at such ring N-atom with a substituent selected from    —COO(C₁-C₄)alkyl and (C₁-C₄)alkyl, preferably a (C₁-C₂)alkyl group,    optionally substituted by one, two or three substituents    independently selected from OH and halo, or-   (ii) at one or both ring C-atoms next to the ring N-atom by up to    four (C₁-C₂)alkyl groups,    or a pharmaceutically acceptable salt or solvate thereof.

In a preferred embodiment thereof, R³ is —NHR⁴, wherein R⁴ is—(C₀-C₁)alkyl-heterocyclyl³; wherein heterocyclyl³ is selected fromazetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl,tetrahydropyranyl, oxepanyl and azepanyl.

In a further preferred embodiment thereof, R³ is —NHR⁴, wherein R⁴ isselected from oxetan-3-yl, 1-methyl-pyrrolidin-3-yl,tetrahydrofuran-3-yl, (tetrahydrofuran-3-yl)-methyl,2,2,6,6-tetramethylpiperidin-4-yl, 1-methyl-piperidin-4-yl, andtetrahydropyran-4-yl.

In a further aspect, the present invention relates to a compound of theformula (I), wherein

R¹ is —CR⁹═N—O—R¹⁰, wherein

-   -   R⁹ is methyl; and    -   R¹⁰ is hydrogen or 2-hydroxy-ethyl;        R² is hydrogen or fluoro, and        R³ is optionally substituted-heterocyclyl¹ as defined herein;        or a pharmaceutically acceptable salt or solvate thereof.

In a preferred embodiment thereof, R³ is heterocyclyl¹ which is a 5 or6-membered saturated N-heterocyclic ring attached via the N-atom andoptionally comprises one additional ring heteroatom independentlyselected from N and O in a position other than adjacent to the linking Natom, and optionally substituted with a substituent selected from —OH,—N(methyl)₂, methoxy and methyl. Preferably, R³ is heterocyclyl¹,wherein heterocyclyl¹ is selected from morpholin-4-yl,4-methoxypiperidin-1-yl, 4-hydroxypiperidin-1-yl,N,N-dimethylamino-pyrrolidin-1-yl, 4-methyl-piperazin-1-yl and3,5-dimethylpiperazin-1-yl.

Various embodiments of the invention are described herein. It will berecognized that features specified in each embodiment may be combinedwith other specified features to provide further embodiments.

In a particular embodiment, the invention provides one or moreindividual compounds as those listed in the Examples section below, or apharmaceutically acceptable salt or solvate thereof.

In another embodiment the invention provides a compound of the formula(I), which is selected from the following compounds:

-   No. 1 tert-Butyl    1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-ylcarbamate-   No. 2    1-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-amine-   No. 3    (S)—N,N-Dimethyl-1-(6-(6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-amine-   No. 4 (S)-tert-Butyl    3-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)pyrrolidine-1-carboxylate-   No. 5    (S)-6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(pyrrolidin-3-yl)quinolin-3-amine-   No. 6    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-((4-methylpiperazin-1-yl)methyl)quinoline-   No. 7    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin-3-amine-   No. 8    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(1-methyl-piperidin-4-yl)-amine-   No. 9 tert-Butyl    1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-3-ylcarbamate-   No. 10    1-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-3-amine-   No. 11    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-((tetrahydrofuran-3-yl)methyl)quinolin-3-amine-   No. 12    6-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2-oxa-6-azaspiro[3.3]heptane-   No. 13    (S)-1-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-N,N-dimethylpyrrolidin-3-amine-   No. 14    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)quinoline-   No. 15    (1-Methyl-piperidin-4-yl)-{6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-amine-   No. 17    3-(4-Methyl-1,4-diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 18 tert-Butyl    4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-1,4-diazepane-1-carboxylate-   No. 19    3-(1,4-Diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 20 tert-Butyl    1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-4-ylcarbamate-   No. 21    1-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-4-amine-   No. 22 tert-Butyl    4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)piperidine-1-carboxylate-   No. 23    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(piperidin-4-yl)quinolin-3-amine-   No. 24    6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-3-(4-methyl-piperazin-1-yl)-quinoline-   No. 25    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-pyran-4-yl)-amine-   No. 26 tert-Butyl    4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperazine-1-carboxylate-   No. 27    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(piperazin-1-yl)quinoline-   No. 28    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinoline-   No. 29    2-(4-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-1,4-diazepan-1-yl)ethanol-   No. 30    3-(1,4′-Bipiperidin-1′-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 31    3-(1,4′-Bipiperidin-1′-yl)-6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 32    3-(4-Cyclohexylpiperazin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 33    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)quinoline-   No. 34    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-phenylpiperazin-1-yl)quinoline-   No. 35    2-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 35A    (S)-2-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 35B    (R)-2-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 36    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2-methylmorpholine-   No. 37    2,6-Dimethyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 38    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)    quinolin-3-yl)-2,6-dimethylmorpholine-   No. 39 (2S,6R)-tert-Butyl    4-(6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2,6-dimethylpiperazine-1-carboxylate-   No. 40    3-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 41 (2S,6R)-tert-Butyl    2,6-dimethyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperazine-1-carboxylate-   No. 42    3-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 43    3-(4-Methoxypiperidin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 44    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-methoxypiperidin-1-yl)quinoline-   No. 45 (S)-tert-Butyl    4-(6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-3-methylpiperazine-1-carboxylate-   No. 46    (S)-6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(2-methylpiperazin-1-yl)quinoline-   No. 47    2-(6-((6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)-8-oxa-2-azaspiro[4.5]decane-   No. 48    2-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-8-oxa-2-azaspiro[4.5]decane-   No. 49    1-(6-((6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol-   No. 50    1-(6-((8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol-   No. 51    6-[6-(1-Methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-furan-3-yl)-amine-   No. 52    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-furan-3-yl)-amine-   No. 53    2-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)ethanol-   No. 54    2-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)ethanol-   No. 55    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-amine    hydrochloride-   No. 56    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-amine    hydrochloride-   No. 57    4-(6-(6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 58    4-(6-(8-Fluoro-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 59    3-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-morpholine-   No. 60    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-3-methylmorpholine-   No. 61    3-(4,4-Difluoro-piperidin-1-yl)-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline-   No. 62    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(2,2,6,6-tetramethyl    piperidin-4-yl)quinolin-3-amine-   No. 64    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(oxetan-3-yl)    quinolin-3-amine-   No. 67    3-(4,4-Difluoro-piperidin-1-yl)-6-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline-   No. 68    {6-[6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-pyran-4-yl)-amine-   No. 69    4-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 70    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 71    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(oxetan-3-yl)quinolin-3-amine-   No. 72    2-(4-(3-(3-Morpholin-4-yl-quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1H-pyrazol-1-yl)ethanol-   No. 74    3-(4-Methyl-piperazin-1-yl)-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline-   No. 75    4-((6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)methyl)-morpholine-   No. 76    (E)-1-(3-((3-(4-Hydroxypiperidin-1-yl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-ethanone    O-(2-hydroxyethyl)oxime-   No. 77    (E)-1-(3-((3-Morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 78    (E)-1-(3-((3-Morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-(2-hydroxyethyl)oxime-   No. 79    (E)-1-(3-(3-(Morpholin-4-yl-methyl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 80    (E)-1-(3-((3-(Morpholin-4-yl-methyl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-(2-hydroxyethyl)oxime-   No. 81    (S,E)-1-(3-(3-(3-(Dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime-   No. 82    (S,E)-1-(3-(3-(3-(Dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 83    (E)-1-(3-(3-(Tetrahydro-2H-pyran-4-ylamino)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime-   No. 84    (E)-1-(3-(3-(Tetrahydro-2H-pyran-4-ylamino)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 85    (S,E)-1-{3-[3-(3-dimethylamino-pyrrolidin-1-yl)-quinolin-6-ylthio]-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-6-yl}ethanone    O-(2-hydroxy-ethyl)-oxime-   No. 86    (S,E)-1-(3-(3-(4-Methylpiperazin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime

In a further embodiment, the invention provides a compound of theformula (I), which is selected from

-   No. 1 tert-Butyl    1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-ylcarbamate-   No. 2    1-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-amine-   No. 3    N,N-Dimethyl-1-(6-(6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-amine-   No. 4 tert-Butyl    3-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)pyrrolidine-1-carboxylate-   No. 5    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(pyrrolidin-3-yl)quinolin-3-amine-   No. 6    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-((4-methylpiperazin-1-yl)methyl)quinoline-   No. 7    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin-3-amine-   No. 8    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(1-methyl-piperidin-4-yl)-amine-   No. 9 tert-Butyl    1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-3-ylcarbamate-   No. 10    1-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-3-amine-   No. 11    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-((tetrahydrofuran-3-yl)methyl)quinolin-3-amine-   No. 12    6-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2-oxa-6-azaspiro[3.3]heptane-   No. 13    1-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-N,N-dimethylpyrrolidin-3-amine-   No. 14    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)quinoline-   No. 15    (1-Methyl-piperidin-4-yl)-{6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}amine-   No. 17    3-(4-Methyl-1,4-diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 18 tert-Butyl    4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-1,4-diazepane-1-carboxylate-   No. 19    3-(1,4-Diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 20 tert-Butyl    1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-4-ylcarbamate-   No. 21    1-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-4-amine-   No. 22 tert-Butyl    4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)piperidine-1-carboxylate-   No. 23    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(piperidin-4-yl)quinolin-3-amine-   No. 24    6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-3-(4-methyl-piperazin-1-yl)-quinoline-   No. 25    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-pyran-4-yl)-amine-   No. 26 tert-Butyl    4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperazine-1-carboxylate-   No. 27    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(piperazin-1-yl)quinoline-   No. 28    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinoline-   No. 29    2-(4-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-1,4-diazepan-1-yl)ethanol-   No. 30    3-(1,4′-Bipiperidin-1′-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 31    3-(1,4′-Bipiperidin-1′-yl)-6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 32    3-(4-Cyclohexylpiperazin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 33    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)quinoline-   No. 34    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-phenylpiperazin-1-yl)quinoline-   No. 35    2-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 36    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2-methylmorpholine-   No. 37    2,6-Dimethyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 38    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)    quinolin-3-yl)-2,6-dimethylmorpholine-   No. 39 tert-Butyl    4-(6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2,6-dimethylpiperazine-1-carboxylate-   No. 40    3-(3,5-Dimethylpiperazin-1-yl)-6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 41 tert-Butyl    2,6-dimethyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperazine-1-carboxylate-   No. 42    3-(3,5-Dimethylpiperazin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 43    3-(4-Methoxypiperidin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 44    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-methoxypiperidin-1-yl)quinoline-   No. 45 tert-Butyl    4-(6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-3-methylpiperazine-1-carboxylate-   No. 46    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(2-methylpiperazin-1-yl)quinoline-   No. 47    2-(6-((6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)-8-oxa-2-azaspiro[4.5]decane-   No. 48    2-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-8-oxa-2-azaspiro[4.5]decane-   No. 49    1-(6-((6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol-   No. 50    1-(6-((8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol-   No. 51    6-[6-(1-Methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-furan-3-yl)-amine-   No. 52    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-furan-3-yl)-amine-   No. 53    2-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)ethanol-   No. 54    2-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)ethanol-   No. 55    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-amine    hydrochloride-   No. 56    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-amine    hydrochloride-   No. 57    4-(6-(6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 58    4-(6-(8-Fluoro-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 59    3-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-morpholine-   No. 60    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-3-methylmorpholine-   No. 61    3-(4,4-Difluoro-piperidin-1-yl)-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline-   No. 62    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(2,2,6,6-tetramethyl    piperidin-4-yl)quinolin-3-amine-   No. 64    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(oxetan-3-yl)    quinolin-3-amine-   No. 67    3-(4,4-Difluoro-piperidin-1-yl)-6-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline-   No. 68    {6-[6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-pyran-4-yl)-amine-   No. 69    4-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 70    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 71    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(oxetan-3-yl)quinolin-3-amine-   No. 72    2-(4-(3-(3-Morpholin-4-yl-quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1H-pyrazol-1-yl)ethanol-   No. 74    3-(4-Methyl-piperazin-1-yl)-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline-   No. 75    4-((6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)methyl)-morpholine-   No. 76    1-(3-((3-(4-Hydroxypiperidin-1-yl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-ethanone    O-(2-hydroxyethyl)oxime-   No. 77    1-(3-((3-Morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 78    1-(3-((3-Morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-(2-hydroxyethyl)oxime-   No. 79    1-(3-(3-(Morpholin-4-yl-methyl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 80    1-(3-((3-(Morpholin-4-yl-methyl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-(2-hydroxyethyl)oxime-   No. 81    1-(3-(3-(3-(Dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime-   No. 82    1-(3-(3-(3-(Dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 83    1-(3-(3-(Tetrahydro-2H-pyran-4-ylamino)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime-   No. 84    1-(3-(3-(Tetrahydro-2H-pyran-4-ylamino)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 85    1-{3-[3-(3-dimethylamino-pyrrolidin-1-yl)-quinolin-6-ylthio]-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-ethanone    O-(2-hydroxy-ethyl)-oxime-   No. 86    1-(3-(3-(4-Methylpiperazin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime

In a further embodiment, the invention provides a compound of theformula (I), which is selected from

-   No. 2    1-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-amine-   No. 3    (S)—N,N-Dimethyl-1-(6-(6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-amine-   No. 6    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-((4-methylpiperazin-1-yl)methyl)quinoline-   No. 10    1-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-3-amine-   No. 12    6-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2-oxa-6-azaspiro[3.3]heptane-   No. 13    (S)-1-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-N,N-dimethylpyrrolidin-3-amine-   No. 14    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)quinoline-   No. 17    3-(4-Methyl-1,4-diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 19    3-(1,4-Diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 21    1-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-4-amine-   No. 24    6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-3-(4-methyl-piperazin-1-yl)-quinoline-   No. 27    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(piperazin-1-yl)quinoline-   No. 28    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinoline-   No. 29    2-(4-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-1,4-diazepan-1-yl)ethanol-   No. 30    3-(1,4′-Bipiperidin-1′-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 31    3-(1,4′-Bipiperidin-1′-yl)-6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 32    3-(4-Cyclohexylpiperazin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 33    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)quinoline-   No. 34    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-phenylpiperazin-1-yl)quinoline-   No. 35    2-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 35A    (S)-2-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 35B    (R)-2-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 36    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2-methylmorpholine-   No. 37    2,6-Dimethyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 38    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)    quinolin-3-yl)-2,6-dimethylmorpholine-   No. 40    3-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 42    3-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 43    3-(4-Methoxypiperidin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 44    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-methoxypiperidin-1-yl)quinoline-   No. 46    (S)-6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(2-methylpiperazin-1-yl)quinoline-   No. 47    2-(6-((6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)-8-oxa-2-azaspiro[4.5]decane-   No. 48    2-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-8-oxa-2-azaspiro[4.5]decane-   No. 49    1-(6-((6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol-   No. 50    1-(6-((8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol-   No. 57    4-(6-(6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 58    4-(6-(8-Fluoro-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 59    3-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-morpholine-   No. 60    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-3-methylmorpholine-   No. 61    3-(4,4-Difluoro-piperidin-1-yl)-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline-   No. 67    3-(4,4-Difluoro-piperidin-1-yl)-6-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline-   No. 69    4-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 70    4-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 72    2-(4-(3-(3-Morpholin-4-yl-quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1H-pyrazol-1-yl)ethanol-   No. 74    3-(4-Methyl-piperazin-1-yl)-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline-   No. 75    4-((6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)methyl)-morpholine

In a further embodiment, the invention provides a compound of theformula (I), which is selected from

-   No. 76    (E)-1-(3-((3-(4-Hydroxypiperidin-1-yl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-ethanone    O-(2-hydroxyethyl)oxime-   No. 77    (E)-1-(3-((3-Morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 78    (E)-1-(3-((3-Morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-(2-hydroxyethyl)oxime-   No. 81    (S,E)-1-(3-(3-(3-(Dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime-   No. 82    (S,E)-1-(3-(3-(3-(Dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 85    (S,E)-1-{3-[3-(3-dimethylamino-pyrrolidin-1-yl)-quinolin-6-ylthio]-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-ethanone    O-(2-hydroxy-ethyl)-oxime-   No. 86    (S,E)-1-(3-(3-(4-Methylpiperazin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime

In a further embodiment, the invention provides a compound of theformula (I), which is selected from

-   No. 53    2-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)ethanol-   No. 54    2-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)ethanol-   No. 55    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-amine    hydrochloride-   No. 56    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-amine    hydrochloride

In a further embodiment, the invention provides a compound of theformula (I), which is selected from

-   No. 5    (S)-6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(pyrrolidin-3-yl)quinolin-3-amine-   No. 7    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin-3-amine-   No. 8    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(1-methyl-piperidin-4-yl)-amine-   No. 11    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-((tetrahydrofuran-3-yl)methyl)quinolin-3-amine-   No. 15    (1-Methyl-piperidin-4-yl)-{6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-amine-   No. 23    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(piperidin-4-yl)quinolin-3-amine-   No. 25    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-pyran-4-yl)-amine-   No. 51    6-[6-(1-Methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl)-(tetrahydro-furan-3-yl)-amine-   No. 52    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-furan-3-yl)-amine-   No. 62    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(2,2,6,6-tetramethyl    piperidin-4-yl)quinolin-3-amine-   No. 64    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(oxetan-3-yl)    quinolin-3-amine-   No. 68    {6-[6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(tetrahydro-pyran-4-yl)-amine-   No. 71    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(oxetan-3-yl)quinolin-3-amine-   No. 83    (E)-1-(3-(3-(Tetrahydro-2H-pyran-4-ylamino)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime-   No. 84    (E)-1-(3-(3-(Tetrahydro-2H-pyran-4-ylamino)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime

In a further embodiment, the invention provides a compound of theformula (I), which is selected from

-   No. 27    6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(piperazin-1-yl)quinoline-   No. 40    3-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 43    3-(4-Methoxypiperidin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline-   No. 44    6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-methoxypiperidin-1-yl)quinoline-   No. 49    1-(6-((6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol-   No. 50    1-(6-((8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol-   No. 69    4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 70    4-(6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine-   No. 74    3-(4-Methyl-piperazin-1-yl)-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline

In a further embodiment, the invention provides a compound of theformula (I), which is selected from

-   No. 76    (E)-1-(3-((3-(4-hydroxypiperidin-1-yl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-ethanone    O-(2-hydroxyethyl)oxime-   No. 77    (E)-1-(3-((3-morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime-   No. 78    (E)-1-(3-((3-morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-(2-hydroxyethyl)oxime-   No. 82    (S,E)-1-(3-(3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    oxime, and-   No. 86    (E)-1-(3-(3-(4-methylpiperazin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone    O-2-hydroxyethyl oxime

In a further embodiment, the invention provides a compound of formula(I), which is selected from

-   No. 8    {6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(1-methyl-piperidin-4-yl)-amine,    and-   No. 15    (1-Methyl-piperidin-4-yl)-{6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-amine.

Further Definitions

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom. Theterm “chiral” refers to molecules which have the property ofnon-superimposability on their mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner. Therefore, the invention includes enantiomers,diastereomers or racemates of the compound. “Enantiomers” are a pair ofstereoisomers that are non-superimposable mirror images of each other. A1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term isused to designate a racemic mixture where appropriate.“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R—Ssystem. When a compound is a pure enantiomer the stereochemistry at eachchiral carbon may be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line. Certaincompounds described herein contain one or more asymmetric centers oraxes and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-.

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possible isomers oras mixtures thereof, for example as pure optical isomers, or as isomermixtures, such as racemates and diastereoisomer mixtures, depending onthe number of asymmetric carbon atoms. The present invention is meant toinclude all such possible isomers, including racemic mixtures,diasteriomeric mixtures and optically pure forms. Optically active (R)-and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. If the compoundcontains a disubstituted cycloalkyl, the cycloalkyl substituent may havea cis- or trans-configuration. All tautomeric forms are also intended tobe included.

Substituents at atoms with unsaturated bonds may, if possible, bepresent in cis-(Z)- or trans-(E)-form. Preferably, the oximes of thepresent invention have the trans-(E)-form.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturateddouble bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g. acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a basic or acidic moiety, by conventional chemicalmethods. Generally, such salts can be prepared by reacting free acidforms of these compounds with a stoichiometric amount of the appropriatebase (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or thelike), or by reacting free base forms of these compounds with astoichiometric amount of the appropriate acid. Such reactions aretypically carried out in water or in an organic solvent, or in a mixtureof the two. Generally, use of non-aqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile is desirable, wherepracticable. Lists of additional suitable salts can be found, e.g., in“Remington's Pharmaceutical Sciences”, 20th ed., Mack PublishingCompany, Easton, Pa., (1985); and in “Handbook of Pharmaceutical Salts:Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH,Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H and ¹⁴C, or those into which non-radioactiveisotopes, such as ²H and ¹³C are present. Such isotopically labelledcompounds are useful in metabolic studies (with ¹⁴C), reaction kineticstudies (with, for example ²H or ³H), detection or imaging techniques,such as positron emission tomography (PET) or single-photon emissioncomputed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies.

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagents in placeof the non-labeled reagent previously employed.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drug stabilizers, binders, excipients, disintegrationagents, lubricants, sweetening agents, flavoring agents, dyes, and thelike and combinations thereof, as would be known to those skilled in theart (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.Mack Printing Company, 1990, pp. 1289-1329). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by c-Met or (ii) associated with c-Met activity,or (iii) characterized by activity (normal or abnormal) of c-Met; or (2)reducing or inhibiting the activity of c-Met; or (3) reducing orinhibiting the expression of c-Met. In another non-limiting embodiment,the term “a therapeutically effective amount” refers to the amount ofthe compound of the present invention that, when administered to a cell,or a tissue, or a non-cellular biological material, or a medium, iseffective to at least partially reducing or inhibiting the activity ofc-Met; or at least partially reducing or inhibiting the expression ofc-Met.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), monkeys, cows, sheep, goats, horses,dogs, cats, rabbits, rats, mice, fish, birds and the like. In certainembodiments, the subject is a primate. In yet other embodiments, thesubject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

“Disease” as used herein includes a disorder or condition.

In the context of the present invention, “c-Met tyrosine kinase mediateddiseases” are especially such disorders that respond in a beneficial way(e.g. amelioration of one or more symptoms, delay of the onset of adisease, up to temporary or complete cure from a disease) to theinhibition of a protein tyrosine kinase, especially inhibition of ac-Met kinase. These disorders include proliferative diseases such astumor diseases and cancer. These disorders further include inflammatoryconditions, such as inflammatory conditions due to an infection. Inparticular, c-Met inhibitors are intended to treat (solid) tumors drivenby high c-Met pathway activity. Met activating kinase mutations, focalamplification of the Met gene, and high expression of its cognateligand, HGF, can all lead to high c-Met pathway activation, which leadsto tumor transformation.

Indications

The compounds of formula (I) in free form or in salt form, exhibitvaluable pharmacological properties, e.g. c-Met kinase inhibitingproperties, e.g. as indicated in in vitro and in vivo tests as providedherewithin and are therefore indicated for therapy.

Therefore, in one embodiment, the invention relates to a compound offormula (I) or a pharmaceutically acceptable salt thereof, for use inmedicine.

In a further embodiment, the invention relates to a compound of formula(I) or a pharmaceutically acceptable salt thereof, for use in thetreatment of one or more c-Met tyrosine kinase mediated disorders ordiseases, preferably for use in the treatment of a proliferative diseaseor an inflammatory condition.

In a further embodiment, the invention relates to the use of a compoundof formula (I) or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of one or more c-Mettyrosine kinase mediated disorders or diseases, preferably for use inthe treatment of a proliferative disease or an inflammatory condition.

In another embodiment, the invention relates to a method of treating ac-Met related disorder or disease in a subject wherein the methodcomprises administering to the subject in need thereof a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. The disorder or condition to be treated ispreferably a proliferative disease such as a cancer or an inflammatorycondition.

In a further related embodiment to several of the above methods,following administration to the subject, these methods can furtherinvolve observing amelioration or retardation of development ormetastasis of the cancer.

In one embodiment of the invention, subjects to be treated with acompound of the invention are preselected via biomarker analysis toidentify patients having tumors driven by high c-Met pathway activity asindicated above.

In a further embodiment of the present invention, compounds of thepresent invention are useful for treating tumors resistant to existingchemotherapies.

Compounds of formula (I) are further useful for treating diseasesassociated with a c-Met-related condition.

As stated above, c-Met tyrosine kinase mediated or related disorders ordiseases in particular refer to a proliferative disease or aninflammatory condition. Proliferative diseases and inflammatoryconditions are defined in more detail below.

A: Proliferative Diseases

Proliferative diseases comprise cancer indications wherein the cancer isselected from the group consisting of brain cancer, stomach cancer,genital cancer, urinary cancer, prostate cancer, bladder cancer(superficial and muscle invasive), breast cancer, cervical cancer, coloncancer, colorectal cancer, glioma (including glioblastoma, anaplasticastrocytoma, oligoastrocytoma, oligodendroglioma), esophageal cancer,gastric and/or gastroesophageal cancer (GC), gastrointestinal cancer,liver cancer, hepatocellular carcinoma (HCC) including childhood HCC,head and neck cancer (including head and neck squamous-cell carcinoma,nasopharyngeal carcinoma (NPC)), Hurthle cell carcinoma, epithelialcancer, skin cancer, melanoma (including malignant melanoma),mesothelioma, lymphoma, myeloma (including multiple myeloma), leukemias,lung cancer (including non-small cell lung cancer (NSCLC) (including allhistological subtypes: adenocarcinoma, squamous cell carcinoma,bronchoalveolar carcinoma, large-cell carcinoma, and adenosquamous mixedtype), small-cell lung cancer), ovarian cancer, pancreatic cancer,prostate cancer, kidney cancer (including but not limited to papillaryrenal cell carcinoma (PRCC)), intestine cancer, renal cell cancer(including hereditary and sporadic papillary renal cell cancer, Type Iand Type II, and clear cell renal cell cancer); sarcomas, in particularosteosarcomas, clear cell sarcomas, and soft tissue sarcomas (includingalveolar and embryonal rhabdomyosarcomas, alveolar soft part sarcomas);thyroid carcinoma (papillary and other subtypes).

In one embodiment, cancer is selected from the group consisting ofstomach cancer, colon cancer, liver cancer, genital cancer, urinarycancer, melanoma, or prostate cancer. In a particular embodiment, thecancer is liver or esophageal cancer.

In one embodiment, cancer refers in particular to solid tumors andmetastasis derived thereof, e.g. hereditary papillary renal cellcarcinoma (PRCC), sporadic forms of PRCC, head and neck cancer, squamouscell carcinoma, gastric carcinoma, pancreatic carcinoma, lung cancer,bladder cancer, breast cancer, leiomyosarcoma, glioblastoma, melanoma,and alveolar soft part sarcoma.

Furthermore, compounds of formula (I) are particularly useful for thetreatment of colon cancer, including metastases, e.g. in the liver, andof non-small-cell lung carcinoma.

Compounds of formula (I) may also be used in the treatment of hereditarypapillary renal carcinoma (Schmidt, L. et al. Nat. Genet. 16, 68-73,1997) and other proliferative diseases in which c-Met is overexpressedor constitutively activated by mutations (Jeffers and Vande Woude.Oncogene 18, 5120-5125, 1999; and reference cited therein) orchromosomal rearrange-ments (e.g. TPR-MET; Cooper et al. Nature 311,29-33, 1984; Park. et al. Cell 45, 895-904, 1986).

B: Inflammatory Conditions:

Inflammatory conditions in the context of the present invention compriseinflammatory condition being due to an infection. In one embodiment, themethod of treatment would be to block pathogen infection. In aparticular embodiment, the infection is a bacterial infection, e.g., aListeria infection. See, e.g., Shen et al. Cell 103: 501-10, (2000)whereby a bacterial surface protein activates c-Met kinase throughbinding to the extracellular domain of the receptor, thereby mimickingthe effect of the cognate ligand HGF/SF. Compounds of formula (I) arefurther useful in the treatment of additional inflammatory disorders andconditions as provided herein or known in the art.

Pharmaceutical Formulations

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) and/or apharmaceutically acceptable salt thereof, as active ingredient inassociation with at least one pharmaceutically acceptable carrier and/ordiluent. In particular, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof, and one ormore pharmaceutically acceptable carriers.

In a further embodiment, the invention relates to a pharmaceuticalcomposition for treatment of a disease, e.g. of a proliferative diseaseor an inflammatory condition, e.g. of a solid tumor in warm-bloodedanimals, including humans, comprising a dose effective in the treatmentof said disease of a compound of the formula (I) as described above or apharmaceutically acceptable salt of such a compound together with apharmaceutically acceptable carrier.

Such pharmaceutical composition can be formulated for particular routesof administration such as oral administration, parenteraladministration, and rectal administration, etc. In addition, thepharmaceutical compositions of the present invention can be made up in asolid form (including without limitation capsules, tablets, pills,granules, powders or suppositories), or in a liquid form (includingwithout limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifiers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

-   a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,    cellulose and/or glycine;-   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or    calcium salt and/or polyethyleneglycol; for tablets also-   c) binders, e.g., magnesium aluminum silicate, starch paste,    gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose    and/or polyvinylpyrrolidone; if desired-   d) disintegrants, e.g., starches, agar, alginic acid or its sodium    salt, or effervescent mixtures; and/or-   e) absorbents, colorants, flavors and sweeteners.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques. Tablets may be either film coated or enteric coatedaccording to methods known in the art. Tablets may be coated orformulated in a particular way to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

Dosages

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated, the route ofadministration; the renal and hepatic function of the patient; and theparticular compound employed. A physician, clinician or veterinarian ofordinary skill can readily determine the effective amount of each of theactive ingredients necessary to prevent, treat or inhibit the progressof the disorder or disease. Optimal precision in achieving concentrationof drug within the range that yields efficacy without toxicity requiresa regimen based on the kinetics of the drug's availability to targetsites. This involves a consideration of the distribution, equilibrium,and elimination of a drug.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

Combinations

The compound of the present invention may be used in combinationtherapy, i.e. administered either simultaneously with, or before orafter, one or more other therapeutic agents. The compound of the presentinvention may be administered separately, by the same or different routeof administration, or together in the same pharmaceutical composition asthe other agents.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition mediated by c-Met tyrosine kinase. Products provided as acombined preparation include a composition comprising the compound offormula (I) and the other therapeutic agent(s) together in the samepharmaceutical composition, or the compound of formula (I) and the othertherapeutic agent(s) in separate form, e.g. in the form of a kit.

Accordingly, in one embodiment, the present invention relates to acombination comprising a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof as definedin the present invention, and one or more additional therapeuticallyactive agents.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above. Inparticular, the present invention refers to a pharmaceutical compositioncomprising (i) a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof as definedherein, (ii) one or more pharmaceutically acceptable carriers, and (iii)one or more additional therapeutically active agents.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

A compound of formula (I) can besides or in addition be administeredespecially for tumor therapy in combination with chemotherapy,radiotherapy, immunotherapy, photodynamic therapy, surgicalintervention, implants, e.g. with corticosteroids or hormones, or acombination of these. Long-term therapy is equally possible as isadjuvant therapy in the context of other treatment strategies, asdescribed above. Other possible treatments are therapy to maintain thepatient's status after tumor regression, or even chemopreventivetherapy, for example in patients at risk.

More general, a compound of the formula (I) may be used in combinationwith other antiproliferative compounds. Such antiproliferative compoundsinclude, but are not limited to aromatase inhibitors; antiestrogens;anti-androgens; gonadorelin agonists; topoisomerase I inhibitors;topoisomerase II inhibitors; microtubule active compounds; alkylatingcompounds; histone deacetylase inhibitors; antineoplasticantimetabolites; platin compounds; compounds targeting/decreasing aprotein or lipid kinase activity; compoundstargeting/decreasing/inhibiting a protein or lipid phosphatase activity;further anti-angiogenic compounds; compounds which induce celldifferentiation processes; compounds targeting VEGF and/or VEGFR;cyclooxygenase inhibitors; bisphosphonates; mTOR inhibitors; heparanaseinhibitors; biological response modifiers; telomerase inhibitors;inhibitors of Ras oncogenic isoforms; methionine aminopeptidaseinhibitors; proteasome inhibitors; matrix metalloproteinase (MMP)inhibitors; compounds used in the treatment of hematologic malignancies;compounds which target, decrease or inhibit the activity of FMS-liketyrosine kinase receptors (Flt-3R); Hsp90 inhibitors; kinesin spindleprotein inhibitors; MEK inhibitors; EDG binders; antileukemia compounds;ribonucleotide reductase inhibitors; antiproliferative antibodies;S-adenosylmethionine decarboxylase inhibitors; angiostatic steroids;somatostatin receptor antagonists; corticosteroids; otherchemotherapeutic compounds (as defined below); and photosensitizingcompounds.

The term “aromatase inhibitor” as used herein relates to a compoundwhich inhibits the estrogen production, i.e. the conversion of thesubstrates androstenedione and testosterone to estrone and estradiol,respectively. The term includes, but is not limited to steroids,especially atamestane, exemestane and formestane and, in particular,non-steroids, especially aminoglutethimide, roglethimide,pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole,fadrozole, anastrozole and letrozole. Exemestane can be administered,e.g., in the form as it is marketed, e.g. under the trademark AROMASIN.Formestane can be administered, e.g., in the form as it is marketed,e.g. under the trademark LENTARON. Fadrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark AFEMA.Anastrozole can be administered, e.g., in the form as it is marketed,e.g. under the trademark ARIMIDEX. Letrozole can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FEMARA or FEMAR.Aminoglutethimide can be administered, e.g., in the form as it ismarketed, e.g. under the trademark ORIMETEN. A combination of theinvention comprising a chemotherapeutic agent which is an aromataseinhibitor is particularly useful for the treatment of hormone receptorpositive tumors, e.g. breast tumors.

The term “antiestrogen” as used herein relates to a compound whichantagonizes the effect of estrogens at the estrogen receptor level. Theterm includes, but is not limited to tamoxifen, fulvestrant, raloxifeneand raloxifene hydrochloride. Tamoxifen can be administered, e.g., inthe form as it is marketed, e.g. under the trademark NOLVADEX.Raloxifene hydrochloride can be administered, e.g., in the form as it ismarketed, e.g. under the trademark EVISTA. Fulvestrant can be formulatedas disclosed in U.S. Pat. No. 4,659,516 or it can be administered, e.g.,in the form as it is marketed, e.g. under the trademark FASLODEX. Acombination of the invention comprising a chemotherapeutic agent whichis an antiestrogen is particularly useful for the treatment of estrogenreceptor positive tumors, e.g. breast tumors.

The term “anti-androgen” as used herein relates to any substance whichis capable of inhibiting the biological effects of androgenic hormonesand includes, but is not limited to, bicalutamide (CASODEX), which canbe formulated, e.g. as disclosed in U.S. Pat. No. 4,636,505.

The term “gonadorelin agonist” as used herein includes, but is notlimited to abarelix, goserelin and goserelin acetate. Goserelin isdisclosed in U.S. Pat. No. 4,100,274 and can be administered, e.g., inthe form as it is marketed, e.g. under the trademark ZOLADEX. Abarelixcan be formulated, e.g. as disclosed in U.S. Pat. No. 5,843,901.

The term “topoisomerase I inhibitor” as used herein includes, but is notlimited to topotecan, gimatecan, irinotecan, camptothecian and itsanalogues, 9-nitrocamptothecin and the macromolecular camptothecinconjugate PNU-166148 (compound A1 in WO99/17804). Irinotecan can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark CAMPTOSAR. Topotecan can be administered, e.g., in the form asit is marketed, e.g. under the trademark HYCAMTIN.

The term “topoisomerase II inhibitor” as used herein includes, but isnot limited to the anthracyclines such as doxorubicin (includingliposomal formulation, e.g. CAELYX), daunorubicin, epirubicin,idarubicin and nemorubicin, the anthraquinones mitoxantrone andlosoxantrone, and the podophillotoxines etoposide and teniposide.Etoposide can be administered, e.g. in the form as it is marketed, e.g.under the trademark ETOPOPHOS. Teniposide can be administered, e.g. inthe form as it is marketed, e.g. under the trademark VM 26-BRISTOL.Doxorubicin can be administered, e.g. in the form as it is marketed,e.g. under the trademark ADRIBLASTIN or ADRIAMYCIN. Epirubicin can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark FARMORUBICIN. Idarubicin can be administered, e.g. in the formas it is marketed, e.g. under the trademark ZAVEDOS. Mitoxantrone can beadministered, e.g. in the form as it is marketed, e.g. under thetrademark NOVANTRON.

The term “microtubule active compound” relates to microtubulestabilizing, microtubule destabilizing compounds and microtublinpolymerization inhibitors including, but not limited to taxanes, e.g.paclitaxel and docetaxel, vinca alkaloids, e.g., vinblastine, especiallyvinblastine sulfate, vincristine especially vincristine sulfate, andvinorelbine, discodermolides, cochicine and epothilones and derivativesthereof, e.g. epothilone B or D or derivatives thereof. Paclitaxel maybe administered e.g. in the form as it is marketed, e.g. TAXOL.Docetaxel can be administered, e.g., in the form as it is marketed, e.g.under the trademark TAXOTERE. Vinblastine sulfate can be administered,e.g. in the form as it is marketed, e.g. under the trademark VINBLASTIN.Vincristine sulfate can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FARMISTIN. Discodermolide can beobtained, e.g., as disclosed in U.S. Pat. No. 5,010,099. Also includedare Epothilone derivatives which are disclosed in WO 98/10121, U.S. Pat.No. 6,194,181, WO 98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and WO00/31247. Especially preferred are Epothilone A and/or B.

The term “alkylating compound” as used herein includes, but is notlimited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNUor Gliadel). Cyclophosphamide can be administered, e.g., in the form asit is marketed, e.g. under the trademark CYCLOSTIN. Ifosfamide can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark HOLOXAN.

The term “histone deacetylase inhibitors” or “HDAC inhibitors” relatesto compounds which inhibit the histone deacetylase and which possessantiproliferative activity. This includes compounds disclosed in WO02/22577, especiallyN-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamideand pharmaceutically acceptable salts thereof. It further especiallyincludes Suberoylanilide hydroxamic acid (SAHA). Compounds which target,decrease or inhibit activity of histone deacetylase (HDAC) inhibitorssuch as sodium butyrate and suberoylanilide hydroxamic acid (SAHA)inhibit the activity of the enzymes known as histone deacetylases.Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228),Trichostatin A and compounds disclosed in U.S. Pat. No. 6,552,065, inparticular,N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof andN-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide,or a pharmaceutically acceptable salt thereof, especially the lactatesalt.

The term “antineoplastic antimetabolite” includes, but is not limitedto, 5-Fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylatingcompounds, such as 5-azacytidine and decitabine, methotrexate andedatrexate, and folic acid antagonists such as pemetrexed. Capecitabinecan be administered, e.g., in the form as it is marketed, e.g. under thetrademark XELODA. Gemcitabine can be administered, e.g., in the form asit is marketed, e.g. under the trademark GEMZAR.

The term “platin compound” as used herein includes, but is not limitedto, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatincan be administered, e.g. in the form as it is marketed, e.g. under thetrademark CARBOPLAT. Oxaliplatin can be administered, e.g., in the formas it is marketed, e.g. under the trademark ELOXATIN.

The term “compounds targeting/decreasing a protein or lipid kinaseactivity”; as used herein includes, but is not limited to, other serineand/or threonine kinase inhibitors or lipid kinase inhibitors, inparticular also other c-Met tyrosine kinase inhibitors, e.g.

-   a) compounds targeting, decreasing or inhibiting the activity of the    platelet-derived growth factor-receptors (PDGFR), such as compounds    which target, decrease or inhibit the activity of PDGFR, especially    compounds which inhibit the PDGF receptor, e.g. a    N-phenyl-2-pyrimidine-amine derivative, e.g. imatinib, SU101, SU6668    and GFB-111;-   b) compounds targeting, decreasing or inhibiting the activity of the    fibroblast growth factor-receptors (FGFR);-   c) compounds targeting, decreasing or inhibiting the activity of the    insulin-like growth factor receptor I (IGF-IR), such as compounds    which target, decrease or inhibit the activity of IGF-IR, especially    compounds which inhibit the kinase activity of IGF-I receptor, such    as those compounds disclosed in WO 02/092599, or antibodies that    target the extracellular domain of IGF-I receptor or its growth    factors;-   d) compounds targeting, decreasing or inhibiting the activity of the    Trk receptor tyrosine kinase family, or ephrin kinase family    inhibitors;-   e) compounds targeting, decreasing or inhibiting the activity of the    Axl receptor tyrosine kinase family;-   f) compounds targeting, decreasing or inhibiting the activity of the    Ret receptor tyrosine kinase;-   g) compounds targeting, decreasing or inhibiting the activity of the    Kit/SCFR receptor tyrosine kinase, e.g. imatinib;-   h) compounds targeting, decreasing or inhibiting the activity of the    C-kit receptor tyrosine kinases—(part of the PDGFR family), such as    compounds which target, decrease or inhibit the activity of the    c-Kit receptor tyrosine kinase family, especially compounds which    inhibit the c-Kit receptor, e.g. imatinib;-   i) compounds targeting, decreasing or inhibiting the activity of    members of the c-Abl family, their gene-fusion products (e.g.    BCR-Abl kinase) and mutants, such as compounds which target decrease    or inhibit the activity of c-Abl family members and their gene    fusion products, e.g. a N-phenyl-2-pyrimidine-amine derivative, e.g.    imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410;    PD173955 from ParkeDavis; or dasatinib (BMS-354825)-   j) compounds targeting, decreasing or inhibiting the activity of    members of the protein kinase C(PKC) and Raf family of    serine/threonine kinases, members of the MEK, SRC, JAK, FAK, PDK1,    PKB/Akt, and Ras/MAPK family members, and/or members of the    cyclin-dependent kinase family (CDK) and are especially those    staurosporine derivatives disclosed in U.S. Pat. No. 5,093,330, e.g.    midostaurin; examples of further compounds include e.g. UCN-01,    safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO    318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196;    isochinoline compounds such as those disclosed in WO 00/09495; FTIs;    PD184352 or QAN697 (a PI-3K inhibitor) or BEZ235 (a PI-3K inhibitor)    or AT7519 (CDK inhibitor);-   k) compounds targeting, decreasing or inhibiting the activity of    protein-tyrosine kinase inhibitors, such as compounds which target,    decrease or inhibit the activity of protein-tyrosine kinase    inhibitors include imatinib mesylate (GLEEVEC) or tyrphostin. A    tyrphostin is preferably a low molecular weight (Mr<1500) compound,    or a pharmaceutically acceptable salt thereof, especially a compound    selected from the benzylidenemalonitrile class or the    5-arylbenzenemalonirile or bisubstrate quinoline class of compounds,    more especially any compound selected from the group consisting of    Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG    1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+)    enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and    adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid    adamantyl ester; NSC 680410, adaphostin);-   l) compounds targeting, decreasing or inhibiting the activity of the    epidermal growth factor family of receptor tyrosine kinases (EGFR,    ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants,    such as compounds which target, decrease or inhibit the activity of    the epidermal growth factor receptor family are especially    compounds, proteins or antibodies which inhibit members of the EGF    receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and    ErbB4 or bind to EGF or EGF related ligands, and are in particular    those compounds, proteins or monoclonal antibodies generically and    specifically disclosed in WO 97/02266, e.g. the compound of ex. 39,    or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787    722, EP 0 837 063, U.S. Pat. No. 5,747,498, WO 98/10767, WO    97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/30347    (e.g. compound known as CP 358774), WO 96/33980 (e.g. compound    ZD 1839) and WO 95/03283 (e.g. compound ZM105180); e.g. trastuzumab    (Herceptin™), cetuximab (Erbitux™) Iressa, Tarceva, OSI-774,    CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3    or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives which are    disclosed in WO 03/013541; and-   m) compounds targeting, decreasing or inhibiting the activity of the    c-Met receptor, such as compounds which target, decrease or inhibit    the activity of c-Met, especially compounds which inhibit the kinase    activity of c-Met receptor, or antibodies that target the    extracellular domain of c-Met or bind to HGF; and-   n) compounds targeting, decreasing or inhibiting the activity of the    Ron receptor tyrosine kinase.

The term “protein or lipid phosphatase activity” as used hereinincludes, but is not limited to inhibitors of phosphatase 1, phosphatase2A, or CDC25, e.g. okadaic acid or a derivative thereof.

The term “further anti-angiogenic compounds” as used herein includes,but is not limited to compounds having another mechanism for theiractivity, e.g. unrelated to protein or lipid kinase inhibition e.g.thalidomide (THALOMID) and TNP-470.

The term “Compounds which induce cell differentiation processes”includes, but is not limited to e.g. retinoic acid, α- γ- orδ-tocopherol or α- γ- or δ-tocotrienol.

“Compounds targeting VEGF and/or VEGFR” include, but are not limited to,compounds, proteins or monoclonal antibodies targeting VEGF/VEGFR suchas disclosed in WO 98/35958, e.g.1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceuticallyacceptable salt thereof, e.g. the succinate (also named PTK787/ZK222584), or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO00/27819 and EP 0 769 947; those as described by Prewett et al, CancerRes, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc Natl Acad Sci USA,Vol. 93, pp. 14765-14770 (1996); Zhu et al., Cancer Res, Vol. 58, pp.3209-3214 (1998); and Mordenti et al., Toxicol Pathol, Vol. 27, No. 1,pp. 14-21 (1999); in WO 00/37502 and WO 94/10202; ANGIOSTATIN, describedby O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994); ENDOSTATIN,described by O'Reilly et al., Cell, Vol. 88, pp. 277-285 (1997);anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; oranti-VEGF antibodies or anti-VEGF receptor antibodies, e.g. rhuMAb andRHUFab, VEGF aptamer e.g. Macugon; FLT-4 inhibitors, FLT-3 inhibitors,VEGFR-2 IgG1 antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™)

The term “cyclooxygenase inhibitor” as used herein includes, but is notlimited to, e.g. Cox-2 inhibitors, 5-alkyl substituted2-arylaminophenylacetic acid and derivatives, such as celecoxib(CELEBREX), rofecoxib (VIOXX), etoricoxib, valdecoxib or a5-alkyl-2-arylaminophenylacetic acid, e.g.5-methyl-2-(2′-chloro-6′-fluoroanilino)phenyl acetic acid, lumiracoxib.

The term “bisphosphonates” as used herein includes, but is not limitedto, etridonic, clodronic, tiludronic, pamidronic, alendronic,ibandronic, risedronic and zoledronic acid. “Etridonic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark DIDRONEL. “Clodronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark BONEFOS. “Tiludronicacid” can be administered, e.g., in the form as it is marketed, e.g.under the trademark SKELID. “Pamidronic acid” can be administered, e.g.in the form as it is marketed, e.g. under the trademark AREDIA™.“Alendronic acid” can be administered, e.g., in the form as it ismarketed, e.g. under the trademark FOSAMAX. “Ibandronic acid” can beadministered, e.g., in the form as it is marketed, e.g. under thetrademark BONDRANAT. “Risedronic acid” can be administered, e.g., in theform as it is marketed, e.g. under the trademark ACTONEL. “Zoledronicacid” can be administered, e.g. in the form as it is marketed, e.g.under the trademark ZOMETA.

The term “mTOR inhibitors” relates to compounds which inhibit themammalian target of rapamycin (mTOR) and which possess antiproliferativeactivity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779and ABT578.

The term “heparanase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit heparin sulfate degradation. The termincludes, but is not limited to, PI-88.

The term “biological response modifier” as used herein refers to alymphokine or interferons, e.g. interferon γ.

The term “inhibitor of Ras oncogenic isoforms”, e.g. H-Ras, K-Ras, orN-Ras, as used herein refers to compounds which target, decrease orinhibit the oncogenic activity of Ras e.g. a “farnesyl transferaseinhibitor” e.g. L-744832, DK8G557 or R115777 (Zarnestra).

The term “telomerase inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of telomerase. Compounds whichtarget, decrease or inhibit the activity of telomerase are especiallycompounds which inhibit the telomerase receptor, e.g. telomestatin.

The term “methionine aminopeptidase inhibitor” as used herein refers tocompounds which target, decrease or inhibit the activity of methionineaminopeptidase. Compounds which target, decrease or inhibit the activityof methionine aminopeptidase are e.g. bengamide or a derivative thereof.

The term “proteasome inhibitor” as used herein refers to compounds whichtarget, decrease or inhibit the activity of the proteasome. Compoundswhich target, decrease or inhibit the activity of the proteasome includee.g. Bortezomid (Velcade™) and MLN 341.

The term “matrix metalloproteinase inhibitor” or (“MMP” inhibitor) asused herein includes, but is not limited to, collagen peptidomimetic andnonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamatepeptidomimetic inhibitor batimastat and its orally bioavailable analoguemarimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551)BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term “compounds used in the treatment of hematologic malignancies”as used herein includes, but is not limited to, FMS-like tyrosine kinaseinhibitors e.g. compounds targeting, decreasing or inhibiting theactivity of FMS-like tyrosine kinase receptors (Flt-3R); interferon,1-b-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitorse.g. compounds which target, decrease or inhibit anaplastic lymphomakinase.

The term “Compounds which target, decrease or inhibit the activity ofFMS-like tyrosine kinase receptors (Flt-3R)” are especially compounds,proteins or antibodies which inhibit members of the Flt-3R receptorkinase family, e.g. PKC412, midostaurin, a staurosporine derivative,SU11248 and MLN518.

The term “HSP90 inhibitors” as used herein includes, but is not limitedto, compounds targeting, decreasing or inhibiting the intrinsic ATPaseactivity of HSP90; degrading, targeting, decreasing or inhibiting theHSP90 client proteins via the ubiquitin proteosome pathway. Compoundstargeting, decreasing or inhibiting the intrinsic ATPase activity ofHSP90 are especially compounds, proteins or antibodies which inhibit theATPase activity of HSP90 e.g., 17-allylamino, 17-demethoxygeldanamycin(17AAG, 17-DMAG), a geldanamycin derivative; other geldanamycin relatedcompounds; radicicol and HDAC inhibitors; IPI-504, CNF1010, CNF2024,CNF1010 from Conforma Therapeutics; temozolomide (TEMODAL®), AUY922 fromNovartis.

The term “kinesin spindle protein inhibitors” is known in the field andincludes SB715992 or SB743921 from GlaxoSmithKline andpentamidine/chlorpromazine from CombinatoRx;

The term “MEK inhibitors” is known in the field and includes ARRY142886from Array PioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer,leucovorin.

The term “EDG binders” as used herein refers a class ofimmunosuppressants that modulates lymphocyte recirculation, such asFingolimod (FTY720).

The term “antileukemia compounds” includes, for example, Ara-C, apyrimidine analog, which is the 2″-alpha-hydroxy ribose (arabinoside)derivative of deoxycytidine. Also included is the purine analog ofhypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. For thetreatment of acute myeloid leukemia (AML), compounds of formula (I) canbe used in combination with standard leukemia therapies, especially incombination with therapies used for the treatment of AML. In particular,compounds of formula (I) can be administered in combination with, e.g.farnesyl transferase inhibitors and/or other drugs useful for thetreatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16,Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

The term “ribonucleotide reductase inhibitors” includes, but is notlimited to to pyrimidine or purine nucleoside analogs including, but notlimited to, fludarabine and/or cytosine arabinoside (ara-C),6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especiallyin combination with ara-C against ALL) and/or pentostatin.Ribonucleotide reductase inhibitors are especially hydroxyurea or2-hydroxy-1H-isoindole-1,3-dione derivatives, such as PL-1, PL-2, PL-3,PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in Nandy et al., ActaOncologica, Vol. 33, No. 8, pp. 953-961 (1994).

The term “antiproliferative antibodies” as used herein includes, but isnot limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux,bevacizumab (Avastin™) rituximab (Rituxan®), PRO64553 (anti-CD40) and2C4 Antibody. By antibodies is meant e.g. intact monoclonal antibodies,polyclonal antibodies, multispecific antibodies formed from at least 2intact antibodies, and antibodies fragments so long as they exhibit thedesired biological activity.

The term “S-adenosylmethionine decarboxylase inhibitors” as used hereinincludes, but is not limited to the compounds disclosed in U.S. Pat. No.5,461,076.

“Angiostatic steroids” as used herein refers to compounds which block orinhibit angiogenesis, such as, e.g., anecortave, triamcinolone.hydrocortisone, 11-α-epihydrocotisol, cortexolone,17α-hydroxyprogesterone, corticosterone, desoxycorticosterone,testosterone, estrone and dexamethasone.

“Somatostatin receptor antagonists” as used herein refers to compoundswhich target, treat or inhibit the somatostatin receptor such asoctreotide, and SOM230.

“Corticosteroids” as used herein includes, but is not limited tocompounds, such as e.g. fluocinolone, dexamethasone; in particular inthe form of implants.

“Other chemotherapeutic compounds” include, but are not limited to,plant alkaloids, hormonal compounds and antagonists; biological responsemodifiers, preferably lymphokines or interferons; antisenseoligonucleotides or oligonucleotide derivatives; shRNA or siRNA; ormiscellaneous compounds or compounds with other or unknown mechanism ofaction.

“Photosensitizing compounds” are used in the context of “photodynamictherapy” referring to a therapy which uses certain chemicals, i.e.photosensitizing compounds, to treat or prevent cancers. Examples ofphotodynamic therapy include treatment with compounds, such as e.g.VISUDYNE and porfimer sodium.

“Tumor cell damaging approaches” refer to approaches such as ionizingradiation. The term “ionizing radiation” referred to above andhereinafter means ionizing radiation that occurs as eitherelectromagnetic rays (such as X-rays and gamma rays) or particles (suchas alpha and beta particles). Ionizing radiation is provided in, but notlimited to, radiation therapy and is known in the art. See Hellman,Principles of Radiation Therapy, Cancer, in Principles and Practice ofOncology, Devita et al., Eds., 4^(th) Edition, Vol. 1, pp. 248-275(1993).

In certain preferred embodiments, the compounds of the present inventionare co-administered with a chemotherapeutic agent, in particular ananti-cancer agent which is a pathway specific inhibitor. The pathwayspecific inhibitor may be a chemotherapeutic agent or may be a biologicagent, e.g., such as an antibody. Preferred pathway specific inhibitorsinclude, but are not limited to, inhibitors of EGFR, Her-2, Her-3,VEGFR, PDGFR, Ron, IGF-IR, PI-3K, mTOR, and Raf, such as defined above.

Some combinations might be particularly useful for the treatment ofcertain types of proliferative diseases. The following non-exhaustivelist indicates some preferred combinations and the respective diseases:

-   -   a compound of the present invention in combination with an        inhibitor of EGFR (e.g. Iressa™), in particular for the        treatment of NSCLC;    -   a compound of the present invention in combination with an        inhibitor of PI-3K, such as BEZ235 (CAS No. 915019-65-7) from        Novartis, in particular for the treatment of Nasopharyngeal        carcinoma (NPC) and some other cancers;    -   a compound of the present invention in combination with an        inhibitor of mTOR;    -   a compound of the present invention in combination with a        tyrosine protein kinase and/or Raf inhibitor such as Sorafenib,        in particular for the treatment of primary kidney cancer        (advanced renal cell carcinoma) and advanced primary liver        cancer (hepatocellular carcinoma);    -   a compound of the present invention in combination with an VEGFR        inhibitor such as PTK787 or an antibody against the ligand VEGF        such as Avastin®;    -   a compound of the present invention in combination with an PDGFR        inhibitor, e.g. imatinib (STI571 or Glivec®);    -   a compound of the present invention in combination with an mTOR        inhibitors, such as rapamycin and everolimus (RAD001).

In another embodiment, a compound of formula (I) may also be used incombination with one or more further drug substances selected from thegroup of anti-inflammatory drug substances; antagonists of chemokinereceptors; antihistamine drug substances; bronchodilatatory drugsubstances, and nonsteroidal anti-inflammatory drugs (NSAIDs).

The compounds of the invention are also useful as co-therapeuticcompounds for use in combination with such further drug substances,particularly in the treatment of inflammatory diseases such as thosementioned hereinbefore, for example as potentiators of therapeuticactivity of such drugs or as a means of reducing required dosaging orpotential side effects of such drugs. A compound of the invention may bemixed with such other drug substance in a fixed pharmaceuticalcomposition or it may be administered separately (i.e. before,simultaneously with or after the other drug substance). Accordingly, theinvention includes a combination of a compound of formula (I) with oneor more further drug substance selected from the group ofanti-inflammatory drug substances; antihistamine drug substances;bronchodilatatory drug substances, NSAID and antagonists of chemokinereceptors; said compound of the formula (I) and said drug substancebeing in the same or different pharmaceutical composition.

Suitable anti-inflammatory drug substances include steroids, inparticular glucocorticosteroids such as budesonide, beclamethasonedipropionate, fluticasone propionate, ciclesonide or mometasone furoate,or steroids described in WO 02/88167, WO 02/12266, WO 02/100879, WO02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37,39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/035668, WO 03/048181, WO03/062259, WO 03/064445, WO 03/072592, non-steroidal glucocorticoidreceptor agonists such as those described in WO 00/00531, WO 02/10143,WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229; LTB4 antagonistssuch LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB209247 and those described in U.S. Pat. No. 5,451,700; LTD4 antagonistssuch as montelukast and zafirlukast; PDE4 inhibitors such cilomilast(Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp),BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (AlmirallProdesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica),CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554/UM565 (Vernalis),T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo), and those disclosed in WO92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO04/018451, WO 04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO04/045607 and WO 04/037805; A2a agonists such as those disclosed in EP409595A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO 96/02553,WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO02/96462, WO 03/086408, WO 04/039762, WO 04/039766, WO 04/045618 and WO04/046083; A2b antagonists such as those described in WO 02/42298; andbeta-2 adrenoceptor agonists such as albuterol (salbutamol),metaproterenol, terbutaline, salmeterol fenoterol, procaterol, andespecially, formoterol and pharmaceutically acceptable salts thereof,and compounds (in free or salt or solvate form) of formula I of WO0075114, which document is incorporated herein by reference, preferablycompounds of the Examples thereof, especially a compound of formula

and pharmaceutically acceptable salts thereof, as well as compounds (infree or salt or solvate form) of formula I of WO 04/16601, and alsocompounds of WO 04/033412.

Suitable bronchodilatory drugs include anticholinergic or antimuscariniccompounds, in particular ipratropium bromide, oxitropium bromide,tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate, but alsothose described in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840,WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, U.S. Pat.No. 5,171,744, U.S. Pat. No. 3,714,357, WO 03/33495 and WO 04/018422.

Suitable chemokine receptor antagonists include but are not limited toantagonists against CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7,CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, and CXCR5. Inparticular CCR-5 antagonists such as Schering-Plough antagonistsSC-351125, SCH-55700 and SCH-D, Takeda antagonists such asN-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-amin-iumchloride (TAK-770), and CCR-5 antagonists described in U.S. Pat. No.6,166,037 (particularly claims 18 and 19), WO 00/66558 (particularlyclaim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO04/026873.

Suitable antihistamine drug substances include cetirizine hydrochloride,acetaminophen, clemastine fumarate, promethazine, loratidine,desloratidine, diphenhydramine and fexofenadine hydrochloride,activastine, astemizole, azelastine, ebastine, epinastine, mizolastineand tefenadine as well as those disclosed in WO 03/099807, WO 04/026841and JP 2004107299.

The structure of the active agents identified by code nos., generic ortrade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference.

The above-mentioned compounds, which can be used in combination with acompound of the formula (I), can be prepared and administered asdescribed in the art, such as in the documents cited above.

Accordingly, the invention provides the use of a compound of formula (I)for treating a disease or condition mediated by c-Met tyrosine kinase,wherein the medicament is prepared for administration with anothertherapeutic agent as exemplified above. The invention also provides theuse of another therapeutic agent for treating a disease or conditionmediated by c-Met tyrosine kinase, wherein the medicament isadministered with a compound of formula (I).

The invention also provides a compound of formula (I) for use in amethod of treating a disease or condition mediated by c-Met tyrosinekinase, wherein the compound of formula (I) is prepared foradministration with another therapeutic agent.

The invention also provides another therapeutic agent for use in amethod of treating a disease or condition mediated by c-Met tyrosinekinase, wherein the other therapeutic agent is prepared foradministration with a compound of formula (I). The invention alsoprovides a compound of formula (I) for use in a method of treating adisease or condition mediated by c-Met tyrosine kinase, wherein thecompound of formula (I) is administered with another therapeutic agent.The invention also provides another therapeutic agent for use in amethod of treating a disease or condition mediated by c-Met tyrosinekinase, wherein the other therapeutic agent is administered with acompound of formula (I).

The invention also provides the use of a compound of formula (I) fortreating a disease or condition mediated by c-Met tyrosine kinase,wherein the patient has previously (e.g. within 24 hours) been treatedwith another therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition mediatedby c-Met tyrosine kinase, wherein the patient has previously (e.g.within 24 hours) been treated with a compound of formula (I).

In one embodiment, the other therapeutic agent is selected from:

-   -   an EGFR inhibitor such as Iressa™    -   Raf inhibitor such as Sorafenib,    -   PI-3K inhibitor such as BEZ235 (CAS No. 915019-65-7)    -   VEGFR inhibitor such as PTK787    -   VEGF antibody such as Avastin®,    -   PDGFR inhibitor such as STI571 (Glivec®),    -   mTOR inhibitors such as rapamycin and everolimus    -   aromatase inhibitor such as letrozole (Femara®) or anastrozole,    -   microtubule active compound such as paclitaxel or an epothilone,    -   antineoplastic antimetabolite such as gemcitabine or        capecitabine,    -   platin compounds such as carboplatin or cis-platin,    -   bisphosphonates such as AREDIA® or ZOMETA®,    -   HER2 antibodies such as trastuzumab.

Preparation of the Compounds

In another embodiment of the invention, there is provided a method ofmanufacturing a compound of formula (I) and intermediates thereof. Acompound of the formula (I) may be prepared by processes that, thoughnot applied hitherto for the new compounds of the present inventionwhere they thus form new processes, are known per se. The schemesprovide a general overview of synthetic strategies to obtain a compoundof formula (I).

Thus, the invention relates in a further aspect to a manufacturingprocess (a method for manufacturing) a compound of formula (I)comprising at least one reaction step as disclosed herein, andintermediates thereof.

The compounds of the present invention may be prepared by use of knownchemical reactions and procedures. Nevertheless, the following generalpreparative methods are presented to aid the reader in synthesizing thecompounds of formula (I), with specific details provided below in theexperimental section to illustrate working examples. The desiredspecific compounds can be prepared by selecting the appropriate startingmaterials, reactants and reaction conditions.

All variable groups of these methods are as described in the genericdescription if they are not specifically defined below.

It is recognized that compounds of the invention with each claimedoptional functional group may not be prepared by each of thebelow-listed methods. Within the scope of each method, optionalsubstituents may appear on reagents or intermediates which may act asprotecting or otherwise non-participating groups. Utilizing methods wellknown to those skilled in the art, these groups are introduced and/orremoved during the course of the synthetic schemes which provide thecompounds of the present invention.

Typically, the compounds of formula (I) can be prepared according to theSchemes provided infra

Scheme 1 provides details for a synthetic strategy to obtain preferredcompounds of formula (I-A) wherein R¹ is optionally substitutedpyrazolyl, starting from compounds of formula (II.1).

WhereinR^(8a) is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionallysubstituted by a protected OH group;R⁸ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionallysubstituted by one OH group;R² is selected from hydrogen and halo;Z¹ is a leaving group such as Br, I, or triflate (CF₃—SO₂—O— or TfO—) orany other suitable leaving group; andR^(3a) is selected from

-   (i) optionally substituted —(C₀-C₂)alkyl-heterocyclyl¹, wherein free    —OH and —NH₂ groups are adequately protected if necessary,-   (ii) —NHR^(4a), wherein R^(4a) is a protection group such as    t-BOC(N-tert-butoxycarbonyl) or (C₁-C₄)alkyl, said (C₁-C₄)alkyl    being optionally substituted by one, two or three substituents    independently selected from protected OH and halo,    -   or wherein R^(4a) is optionally substituted        —(C₀-C₂)alkyl-heterocyclyl³, wherein free —OH and —NH₂ groups        are adequately protected if necessary; and        R³ is as defined herein for compounds of the present invention.

Depending on the nature of Z¹ and R^(3a), the reaction carried out inStep a might require slightly different reaction conditions. Thereaction product of step A, a compound of formula (I.1) either alreadyrepresents a compound of formula (I) or requires further modificationsof substituents R^(3a) to R³ and/or R^(8a) to R⁸ to deliver a compoundof formula (I-A). Such modifications like the removal of protectiongroups are well known to a person skilled in the art.

Scheme 2 provides details for a synthetic strategy to obtain preferredcompounds of formula (I-B) wherein R¹ is an optionally substituted oximegroup —CR⁹═N—O—R¹⁰, starting from compounds of formula (II.2).

whereinZ² is a leaving group such as Cl, Br, or I or any other suitable leavinggroup;R² is selected from hydrogen and halo;Z¹ is leaving group such as Br, I, or triflate (CF₃—SO₂—O— or TfO—) orany other suitable leaving group; andR^(3a) is selected from

-   (i) optionally substituted —(C₀-C₂)alkyl-heterocyclyl¹, wherein free    OH and NH₂ groups are adequately protected if necessary,-   (ii) —NHR^(4a), wherein R^(4a) is a protection group such as    t-BOC(N-tert-butoxycarbonyl) or (C₁-C₄)alkyl, said (C₁-C₄)alkyl    being optionally substituted by one, two or three substituents    independently selected from protected OH and halo,    -   or wherein R^(4a) is optionally substituted        —(C₀-C₂)alkyl-heterocyclyl³, wherein free —OH and —NH₂ groups        are adequately protected if necessary; and        R³ is as defined herein for compounds of the present invention.

Depending on the nature of Z¹ and R^(3a), the reaction carried out instep A might require slightly different reaction conditions. Thereaction product of step A, a compound of formula (I.2) will then betransformed in the desired oxime derivate (1-B) by steps B and C.Substituent R^(3a) either already represents the desired residue R³ orrequires further modifications such as the removal of protection groupswhich are well known to a person skilled in the art. Such modificationsare preferably carried out before reaction step C.

Scheme 3 provides details for a synthetic strategy to obtain thebuilding blocks (II.1) and (II.2) used in the aforementioned Schemes Aand B.

whereinR² is selected from hydrogen and halo;Z² is a leaving group such as Cl, Br, or I or any other suitable leavinggroup;R^(8a) is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionallysubstituted by a protected OH group; andPG is hydrogen or a suitable protection group.Scheme 4 provides details for a synthetic strategy to obtain thequinoline building blocks (Q) used in the aforementioned Schemes A andB.

WhereinR⁷ is a group such as benzyl or acetyl or any other suitable protectiongroup;Z¹ is a leaving group such as Br, I, or triflate (CF₃—SO₂—O— or TfO—) orany other suitable leaving group; andR^(3a) is selected from

-   (i) optionally substituted —(C₀-C₂)alkyl-heterocyclyl¹, wherein free    —OH and —NH₂ groups are adequately protected if necessary,-   (ii) —NHR^(4a), wherein R^(4a) is a protection group such as    t-BOC(N-tert-butoxycarbonyl) or (C₁-C₄)alkyl, said (C₁-C₄)alkyl    being optionally substituted by one, two or three substituents    independently selected from protected OH and halo,    -   or wherein R^(4a) is optionally substituted        —(C₀-C₂)alkyl-heterocyclyl³, wherein free —OH and —NH₂ groups        are adequately protected if necessary.

The starting materials and reagents in the above scheme are all eitheravailable commercially or can be prepared following literatureprecedents.

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973, in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Third edition, Wiley, New York 1999, in“The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), AcademicPress, London and New York 1981, in “Methoden der organischen Chemie”(Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I,Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit,“Aminosauren, Peptide, Proteine” (Amino acids, Peptides, Proteins),Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in JochenLehmann, “Chemie der Kohlenhydrate: Monosaccharide and Derivate”(Chemistry of Carbohydrates: Monosaccharides and Derivatives), GeorgThieme Verlag, Stuttgart 1974. A characteristic of protecting groups isthat they can be removed readily (i.e. without the occurrence ofundesired secondary reactions) for example by solvolysis, reduction,photolysis or alternatively under physiological conditions (e.g. byenzymatic cleavage).

Accordingly, the present invention relates to a process of manufacturinga compound of formula (I)

wherein R¹, R² and R³ are as defined herein, or a salt or solvatethereof, comprising A) reacting a compound of formula (II)

wherein R^(1.1) is selected from

-   (i) pyrazolyl, optionally substituted by (C₁-C₄)alkyl, said    (C₁-C₄)alkyl being optionally substituted by a protected OH group,    and-   (ii) Z² which is a suitable leaving group;    and R² is selected from hydrogen and halo;    with a compound of formula (III)

wherein Z¹ is a suitable leaving group, andR^(3a) is selected from

-   (i) optionally substituted —(C₀-C₂)alkyl-heterocyclyl¹, wherein any    free —OH and —NH₂ groups are adequately protected if necessary,-   (ii) —NHR^(4a), wherein R^(4a) is a suitable protection group or    (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionally substituted by one,    two or three substituents independently selected from protected OH    and halo,    -   or wherein R^(4a) is optionally substituted        —(C₀-C₂)alkyl-heterocyclyl³, wherein any free —OH and —NH₂        groups are adequately protected if necessary;        in a palladium coupling reaction in the presence of a bidentate        ligand and a base in a polar aprotic solvent at a temperature        from about 80° C. to 120° C. under protective atmosphere, to        deliver a compound of formula (I.0)

B) optional further reaction steps to convert substituent R^(3a) into R³if necessary, andC) optional further reaction steps to convert substituent R^(1.2) intoR¹.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure material.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Celsius. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (=20-133 mbar). Unless otherwise indicated, the reactions takeplace at room temperature (rt). The structure of final products,intermediates and starting materials is confirmed by standard analyticalmethods, e.g., microanalysis and spectroscopic characteristics, e.g.,MS, IR, NMR.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21).

Further, if not indicated otherwise, the analytical and preparative HPLCconditions are as follows:

Method A:

The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)

0-4.0 min: 10% to 90% of methanol

4.0-6.0 min: 90% of methanol

Column: GP C18 3 μm 4.6×30 mm from Sepax.

Oven temperature: 30° C.

Method B:

The flow is 1.2 mL/min of methanol and water (with 0.5% acetic acid)

0-2.0 min: 10% to 90% of methanol

2.0-3.0 min 90% of methanol

Column: GP C18 3 μm 4.6×30 mm from Sepax.

Oven temperature: 30° C.

Method C:

The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)

0-3.0 min: 60% to 90% of methanol

3.0-5.0 min: 90% of methanol

Column: GP C18 3 μm 4.6×30 mm from Sepax.

Oven temperature: 30° C.

Method D:

The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)

0-3.0 min: 10% to 50% of methanol

3.0-4.0 min: 50% of methanol

Column: GP C18 3 μm 4.6×30 mm from Sepax.

Oven temperature: 30° C.

Method E:

The flow is 0.5 mL/min of methanol and water (with 0.5% acetic acid)

0-4.0 min: 10% to 90% of methanol

4.0-8.0 min: 90% of methanol

Column: GP C18 3 μm 4.6×30 mm from Sepax.

Oven temperature: 30° C.

Method F:

The flow is 1 mL/min of Hexane/Ethanol/Diethyleamine 80/20/0.1, v/v/v

Column: AD-H

Oven temperature: 25° C.

Method G:

The flow is 1 mL/min of Hexane/Ethanol/Diethyleamine 70/30/0.1, v/v/v

Column: AD-H

Oven temperature: 25° C.

Method H:

The flow is 1 mL/min of Hexane/Isopropanol/Diethylamine 70/30/0.1, v/v/v

Column: CHIRALPAK OD-H

Oven temperature: 25° C.

Method I:

SFC equipment: Thar SFC Prep 80

The flow is 45 g/min of Methanol/CO₂ 70/30

Column: CHIRALPAK OD-H, 2.0×25 cm

Wave length: UV 254 nm

Oven temperature: 35° C.

Method J:

The flow is 1.2 mL/min of methanol and water (with 0.5% acetic acid)

0-3.0 min: 60% to 90% of methanol

Column: GP C18 3 μm 4.6×30 mm from Sepax.

Oven temperature: 30° C.

Method K

The flow is 1 mL/min of Hexane/Ethanol/Diethyleamine 80/20/0.1, v/v/v

Column: OJ-H

Oven temperature: 25° C.

Method L

SFC equipment: Thar SFC Prep 80

The flow is 45 g/min of Methanol/CO₂ 75/25

Column: CHIRALPAK AD-H, 2.0×25 cm

Wave length: UV 254 nm

Oven temperature: 35° C.

Method M:

The flow is 0.5 mL/min of methanol and water (with 0.5% formic acid)

0-4.0 min: 10% to 90% of methanol

4.0-6.0 min: 90% of methanol

Column: GP C18 3 μm 4.6×30 mm from Sepax.

Oven temperature: 30° C.

Method N:

The flow is 1.5 mL/min of methanol and water (with 0.5% formic acid)

0-2.0 min: 10% to 90% of methanol

2.0-3.0 min 90% of methanol

Column: GP C18 3 μm 4.6×30 mm from Sepax.

Oven temperature: 30° C.

Method O:

The flow is 1.8 mL/min of methanol and water (with 0.5% formic acid)

0-4.0 min: 10% to 95% of methanol

4.0-5.0 min 95% of methanol

Column: GP C18 3 μm 4.6×30 mm from Sepax.

Oven temperature: 30° C.

Method P:

The flow is 1.8 mL/min of acetonitrile (with 0.01% TFA) and water (with0.01% TFA)

0-0.2 min: 5% of acetonitrile

0.2-1.4 min: 5% to 95% of acetonitrile

1.4-3.0 min: 95% of acetonitrile

Column: Xbridge, 3.5 μm, 4.6×50 mm

Oven temperature: 50° C.

Method Q:

SFC equipment: Thar SFC Prep 80

The flow is 45 g/min of Methanol/CO₂ 25/75

Column: CHIRALPAK AS-D, 2.0×25 cm

Wave length: UV 254 nm

Oven temperature: 35° C.

Abbreviations used are those conventional in the art. In particular, inthe following examples, the abbreviations given below are used:

-   AcOH acetic acid-   aq. aqueous-   Ar Argon-   atm. atmosphere-   BINAP 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl-   Bn benzyl-   Boc tert-butoxycarbonyl-   DCC dicyclohexylcarbodiimide-   DCM dichloromethane-   DME 1,2-dimethoxyethane or dimethyl ethylene glycol ether-   DMF N,N-dimethylformamide-   DMSO dimethyl sulfoxide-   eq. equivalent(s)-   Et₂O diethyl ether-   EtOAc or EA ethyl acetate-   EtOH ethanol-   h hour(s)-   HATU 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   Hex Hexane-   HPLC High Performance Liquid Chromatography-   HV high vacuum-   IBX 2-iodoxybenzoic acid-   Isolute Isolute® HM-N by International Solvent Technology Ltd., U.K.-   KO^(t)Bu potassium 2-methylpropan-2-olate (Potassium tert-butoxide)-   LAH lithium aluminium hydride-   LCMS liquid chromatography coupled with mass spectrometry-   LDA lithium diisopropylamide-   MeOH methanol-   min minute(s)-   mL milliliter(s)-   mmol millimol-   MPLC Medium Pressure Liquid Chromatography-   MS-ES electrospray mass spectrometry-   MW microwave-   NBS N-bromosuccinimide-   n-BuLi n-butyllithium-   NMP N-methylpyrrolidinone-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium (0)-   PdCl₂(dppf) 1,1-bis(diphenylphosphino)ferrocenedichloropalladium    (II)-   PdCl₂(Ph₃)₂ dichlorobis(triphenylphosphine)palladium (II)-   R_(f) ratio of fronts in TLC-   rt room temperature-   TBAF tetrabutylammonium fluoride-   TBME methyl tert-butyl ether-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   t_(R) retention time-   UV Ultraviolet-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

The compounds of the present invention can be produced by organicsynthesis methods known to one of ordinary skill in the art as shown inthe following examples.

Syntheses of Intermediates Intermediate A & Intermediate B3-bromoquinolin-6-yl acetate (intermediate A)6-(benzyloxy)-3-bromoquinoline (intermediate B)

Quinolin-6-yl acetate (A.i)

To a solution of quinolin-6-ol (4.5 g, 31.0 mmol) and pyridine (3.01 ml,37.2 mmol) in DCM (50 ml) was added acetyl chloride (2.65 ml, 37.2 mmol)at 0° C. The mixture was then stirred at rt for 8 h. The reaction wasquenched with saturated NaHCO₃ and the mixture was extracted with DCM(30 ml) three times. The combined organic phase was washed with brineand dried over anhydrous MgSO₄, filtered and concentrated to give thetitle compound (5.0 g, 68.9% yield), which was used directly in nextstep. LCMS (method B): [M+H]⁺=188, t_(R)=1.64 min.

3-Bromoquinolin-6-yl acetate (Intermediate A)

To a solution of A.i (5 g, 26.7 mmol) and pyridine (6.48 ml, 80 mmol) inCCl₄ (100 ml) was added Br₂ (4.13 ml, 80 mmol) at 0° C. The resultantbrown suspension was then heated at 90° C. for 3 h. After being cooledto rt, the mixture was diluted with DCM and water. The organic phase wasseparated and washed with water and brine, dried over anhydrous MgSO₄,filtered and concentrated. The residue was purified by silica gelchromatography with Hex/EA (from 100% to 90%) to afford the titlecompound as white solid (3.2 g, 40.5% yield). ¹H-NMR (400 MHz, DMSO-d₆)δ ppm 8.95 (s, 1H), 8.73 (s, 1H), 8.08 (d, 1H), 7.74 (d, 1H), 7.62 (dd,1H), 2.34 (s, 3H). LCMS (method B): [M+H]⁺=267, t_(R)=2.29 min.

3-Bromoquinolin-6-ol (B.i)

A solution of Intermediate A (1 g, 3.76 mmol) and K₂CO₃ (1.04 g, 7.52mmol) in MeOH/H₂O (5 mL/3 mL) was stirred at rt for 2 hours. Thereaction mixture was concentrated under reduced pressure to afford acrude solid which was further purified by washing with water, driedunder vacuum to give the title compound as white solid (760 mg, yield86%). LCMS (method N): [M+H]⁺=224, t_(R)=2.29 min.

6-(Benzyloxy)-3-bromoquinoline (intermediate B)

A solution of B.i (760 mg, 3.39 mmol), benzyl bromide (0.44 mL, 3.73mmol) and K₂CO₃ (563 mg, 4.07 mmol) in acetone (20 mL) was stirred at rtovernight. The reaction mixture was concentrated under reduced pressure.The crude product was purified by chromatography (eluting with 20% EtOAcin haxane) to give the title compound as white solid (970 mg, yield89%). LCMS (method N): [M+H]⁺=314, t_(R)=2.91 min. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.76 (d, 1H), 8.23 (d, 1H), 8.05 (d, 1H), 7.49-7.34 (m,6H), 7.08 (d, 1H), 5.20 (s, 2H).

Building Blocks of Formula (II.1)

Building blocks of formula (II.1) comprising Intermediates C, D, E, Fand G were synthesized according to general Scheme 3, left side.

Intermediate C6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol

2-fluoro-5-(1H-pyrazol-4-yl)pyridine (C.i)

To a solution of 5-bromo-2-fluoropyridine (1.0 g, 5.68 mmol) in dioxane(30 ml) was added tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(1.671 g, 5.68 mmol), Na₂CO₃ (1.205 g, 11.36 mmol) and Pd(Ph₃P)₄ (0.657g, 0.568 mmol). The reaction mixture was stirred at 100° C. under Aratmosphere for overnight. The reaction was cooled and concentrated underreduced pressure. The residue was purified by silica gel chromatography(DCM/MeOH=30/1) to afford the title compound as white solid (0.5 g,44.2% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 13.0 (s, 1H), 8.29 (s,1H), 8.2 (d, 1H), 8.18 (d, 1H), 7.99 (s, 1H), 7.18 (dd, 1H). LCMS(method B): [M+H]⁺=164, t_(R)=1.73 min.

2-hydrazinyl-5-(1H-pyrazol-4-yl)pyridine (C.ii)

To a solution of C.i (0.5 g, 3.06 mmol) in dioxane (10 ml), hydrazinemonohydrate (0.385 ml, 12.26 mmol) was added, and the mixture wasrefluxed for overnight. The reaction was then cooled and concentratedunder reduced pressure. The residue was recrystallized from DCM/MeOH(10/1) to afford the title compound as white solid (0.4 g, 44.0% yield).LCMS (method B): [M+H]⁺=176, t_(R)=0.5 min.

6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (IntermediateC)

C.ii (0.4 g, 2.283 mmol) and di(1H-imidazol-1-yl)meth-anethione (0.407g, 2.283 mmol) were dissolved in DMF (10 ml). The reaction mixture wasstirred at 90° C. for 3 h. The solvent was removed under reducedpressure to afford the crude product, which was recrystallized fromDCM/MeOH (10/1) to afford the title compound as pale yellow solid (0.3g, 52.6% yield). LCMS (method B): [M+H]⁺=218, t_(R)=1.66 min.

Intermediate D8-fluoro-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol

2,3-difluoro-5-(1H-pyrazol-4-yl)pyridine (D.i)

5-bromo-2,3-difluoropyridine (2.0 g, 10.31 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(3.03 g, 10.31 mmol), Na₂CO₃ (2.186 g, 20.62 mmol) and Pd(Ph₃P)₄ (1.191g, 1.031 mmol) were dissolved in dioxane (20 ml). The mixture wasbubbled with Ar for 10 min. The reaction was stirred at 100° C. forovernight, cooled and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (DCM/MeOH=30/1) to afford thetitle compound as white solid (1.0 g, 53.5% yield). LCMS (method B):[M+H]⁺=182, t_(R)=1.98 min.

3-fluoro-2-hydrazinyl-5-(1H-pyrazol-4-yl)pyridine (D.ii)

To a solution of D.i (500 mg, 2.76 mmol) in dioxane (10 ml), hydrazinemonohydrate (0.347 ml, 11.04 mmol) was added. The reaction mixture washeated at reflux for overnight, cooled and concentrated under reducedpressure. The residue was recrystallized from DCM/MeOH (10/1) to affordthe title compound (500 mg, 68.1% yield) as white solid. LCMS (methodB): [M+H]⁺=194, t_(R)=0.5 min.

8-fluoro-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol(Intermediate D)

D.ii (0.4 g, 2.071 mmol) and di(1H-imidazol-1-yl)methanethione (0.369 g,2.071 mmol) were dissolved in DMF (10 ml). The resulting solution wasstirred at 90° C. for 3 h, cooled and concentrated under reducedpressure. The residue was recrystallized from DCM/MeOH (10/1) to affordthe title compound as pale green solid (0.2 g, 28.7% yield). LCMS(method B): [M+H]⁺=236, t_(R)=1.78 min.

Intermediate E6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol

2-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (E.i)

A mixture of 5-bromo-2-fluoropyridine (1.75 g, 9.94 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.069 g, 9.94 mmol), Pd(PPh₃)₄ (1.149 g, 0.994 mmol) and K₂CO₃ (2.75 g,19.89 mmol) in 1,4-dioxane (20 ml) was bubbled with argon for 10 min.The suspension was then stirred at 90° C. for 8 h. The mixture wasfiltered and the filtrate was diluted with EA, washed with water andbrine. The organic phase was dried over anhydrous MgSO₄, filtered andconcentrated. The residue was recrystallized from MeOH to give the titlecompound as white solid (1.2 g, 61.3% yield). ¹H-NMR (400 MHz, DMSO-d₆)δ ppm 8.46 (s, 1H), 8.22 (s, 1H), 8.15 (dd, 1H), 7.93 (s, 1H), 7.18 (dd,1H). LCMS (method B): [M+H]⁺=178, t_(R)=1.80 min.

2-hydrazinyl-5-(1-methyl-1H-pyrazol-4-yl)pyridine (E.ii)

To a solution of E.i (1.0 g, 5.64 mmol) in MeOH (20 ml) was addedhydrazine monohydrate (0.531 ml, 16.93 mmol). The reaction was heated atreflux for 24 h. The solution was concentrated and the precipitateproduced was collected by filtration, washed with EA and dried to affordthe title compound as white solid. (0.9 g, 76% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.21 (s, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7.63 (dd, 1H),7.32 (s, 1H), 6.70 (d, 1H), 4.12 (s, 2H), 3.82 (s, 3H). LCMS (method B):[M+H]⁺=190, t_(R)=0.30 min.

6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol(Intermediate E)

To a suspension of E.ii (1 g, 5.28 mmol) in DMF (15 ml) was addeddi(1H-imidazol-1-yl)methanethione (0.942 g, 5.28 mmol) and the mixturewas stirred at 80° C. for 5 h. The mixture was cooled to rt and theprecipitate produced was collected, washed with DCM and dried to affordthe title compound as yellow solid (0.78 g, 57.4% yield). ¹H-NMR (400MHz, DMSO-d₆) δ ppm 14.4 (s, 1H), 8.35 (d, 2H), 8.00 (s, 1H), 7.76 (d,1H), 7.69 (d, 1H), 3.82 (s, 3H). LCMS (method B): [M+H]⁺=232, t_(R)=1.75min.

Intermediate F8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol

2,3-difluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (F.i)

A mixture of 5-bromo-2,3-difluoropyridine (1.9 g, 9.79 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.038 g, 9.79 mmol), Na₂CO₃ (2.076 g, 19.59 mmol) and Pd(PPh₃)₄ (1.131g, 0.979 mmol) in DMF (8 ml) was bubbled with N₂ for 10 min and was thenheated to 80° C. for 10 h. After being cooled to rt, the mixture wasfiltered and the filtrate was diluted with EA, washed with water andbrine, dried over anhydrous MgSO₄. Filtered and concentrated. Theresidue was purified by silica gel chromatography eluted with Hex/EA(from 100% to 20%) to afford the title compound as a white solid (1.5 g,57.4% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.29 (d, 3H), 7.99 (d,1H), 3.87 (s, 3H). LCMS (method B): [M+H]⁺=196, t_(R)=1.91 min.

3-fluoro-2-hydrazinyl-5-(1-methyl-1H-pyrazol-4-yl)pyridine (F.ii)

To a solution of F.i (1.6 g, 8.20 mmol) in MeOH (25 ml) was addedhydrazine monohydrate (1.029 ml, 32.8 mmol) and the mixture was heatedat 60° C. for 10 h. The reaction was then cooled to rt and theprecipitate produced was collected by filtration and washed with cooledEtOH to afford the title compound (1.2 g, 63.6% yield). LCMS (method B):[M+H]⁺=208, t_(R)=0.27 min.

8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol(Intermediate F)

To a suspension of F.ii (0.8 g, 3.86 mmol) in CHCl₃ (8 ml) was addeddi(1H-imidazol-1-yl)methanethione (0.688 g, 3.86 mmol), and the mixturewas stirred at 90° C. for 5 h. The reaction was then cooled to rt andthe precipitate produced was collected, washed with cool DCM and driedto afford the title compound (0.502 g, 46.9% yield). The product wasused in the next step without further purification. LCMS (method B):[M+H]⁺=250, t_(R)=1.80 min.

Intermediate G6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol

2-fluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridine(G.i)

A mixture of 5-bromo-2-fluoropyridine (176 mg, 1.00 mmol),1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(322 mg, 1.00 mmol), Pd(PPh₃)₄ (115 mg, 0.100 mmol) and Na₂CO₃ (212 mg,2.00 mmol) in 1,4-dioxane (5 ml) was bubbled with N₂ for 10 min and thenstirred at 85° C. for 6 h. After being cooled to rt, the reactionmixture was filtered through celite and the filtrate was diluted withEA. The organic phase was washed with water, brine and dried overanhydrous MgSO₄. Filtered and concentrated to afford the title compound(0.206 g, yield 63.6%), which was used in next step without furtherpurification. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.48 (s, 1H), 8.27 (s,1H), 8.17 (dd, 1H), 7.98 (s, 1H), 7.19 (d, 1H), 4.53 (s, 1H), 4.30 (t,2H), 3.95 (m, 1H), 3.75 (m, 1H), 3.53 (m, 1H), 3.35 (t, 1H), 1.65 (m,1H), 1.57 (m, 1H), 1.40 (m, 4H). LCMS (method B): [M+H]⁺=292, t_(R)=2.16min.

2-hydrazinyl-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridine(G.ii)

To a solution of G.i (800 mg, 2.75 mmol) in MeOH (5 ml) was addedhydrazine monohydrate (0.673 ml, 10.98 mmol) and the mixture was stirredat 70° C. for 8 h. The solvent was removed to afford the title compound(500 mg, 60.2% yield). LCMS (method B): [M+H]⁺=304, t_(R)=0.26 min.

6-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine-3-thiol(Intermediate G)

To a solution of G.ii (180 mg, 0.593 mmol) in DMF (5 ml) was addeddi(1H-imidazol-1-yl)methanethione (106 mg, 0.593 mmol) and the mixturewas heated at 50° C. for 5 h. The resultant suspension was diluted withwater and extracted with DCM. The extract was washed with water, brineand dried over anhydrous MgSO₄. Filtered and concentrated. The residuewas purified by silica gel chromatography (DCM/MeOH: 100% to 95%) toafford a yellow solid. (0.12 g, 25.7% yield). LCMS (method B):[M+H]⁺=346, t_(R)=2.10 min.

Building Blocks of Formula (II.2)

Building blocks of formulate (II.2) comprising Intermediates H and Iwere synthesized according to general Scheme 3, right side.

Intermediate H 6-Bromo-8-fluoro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol

5-Bromo-3-fluoro-2-hydrazinylpyridine (H.i)

To a solution of 5-bromo-2,3-difluoropyridine (15 g, 77 mmol)) in EtOH(250 ml) was added hydrazine hydrate (19.36 g, 387 mmol), the mixturewas heated to reflux and stirred overnight (16 hr). The solvent of thereaction mixture was evaporated about half under reduced pressure, thencooling in an ice bath there precipitation was occurred, filtered andwashed the product with a minimum of EtOH and water, dried in vacuum toobtain pure desired product as white powder (15 g, yield 94%). LCMS(method A): [M+H]⁺=206.0, 208.0, t_(R)=1.01 min.

6-Bromo-8-fluoro-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate H)

To a solution of H.i (15 g, 72.8 mmol) in anhydrous DMF (150 ml) wasadded di(1H-imidazol-1-yl)methanethione (12.98 g, 72.8 mmol) by portionsat 0° C., after the addition was completed, the mixture was heated to85° C. and stirred for about 3 hr. The solvent was evaporated underreduced pressure and the residue was recrystallized from DCM/MeOH (5:1)to give pure desired product as yellow solid (3.5 g, yield 19.3%). LCMS(method A): [M−H]⁻=246, 248, t_(R)=2.10 min. ¹H-NMR (400 MHz, DMSO-d₆) δppm 14.98 (s, 1H), 8.24 (s, 1H), 7.75 (d, 1H).

Intermediate I 6-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3-thiol

5-bromo-2-hydrazinylpyridine (I.i)

To a solution of 5-bromo-2-fluoropyridine (10 g, 56.8 mmol) in EtOH (120ml) was added hydrazine hydrate (14.22 g, 284 mmol), the mixture washeated to reflux and stirred overnight (16 hr). The solvent of thereaction mixture was evaporated about half under reduced pressure, thencooling in an ice bath there precipitation was occurred, filtered andwashed the product with a minimum of EtOH and water, dried in vacuum toobtain pure desired product as white powder (10.2 g, yield 91%). LCMS(method A): [M+H]⁺=188.1, 190.1, t_(R)=0.62 min.

6-Bromo-[1,2,4]triazolo[4,3-a]pyridine-3-thiol (Intermediate I)

To a solution of I.i (10.2 g, 54.2 mmol) in anhydrous DMF (150 ml) wasadded di(1H-imidazol-1-yl)methanethione (9.67 g, 54.2 mmol) by portionsat 0° C., after the addition was completed, the mixture was heated to85° C. and stirred for about 3 hr. The solvent was evaporated underreduced pressure and the residue was recrystallized from DCM/MeOH (5:1)to give pure desired product as yellow solid (7.3 g, yield 55.6%). LCMS(method A): [M−H]⁻=227.9, 230, t_(R)=2.03 min. ¹H-NMR (400 MHz, DMSO-d₆)δ ppm 14.69 (s, 1H), 8.38 (s, 1H), 7.67 (d, 1H), 7.41 (d, 1H).

Building Blocks of Formula (Q)

Building blocks of formulate (Q) comprising Intermediates Q1 to Q36 aresynthesized according to general Scheme 4 starting from Intermediates Aor B.

Intermediate Q13-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)quinolin-6-yltrifluoromethanesulfonate

tert-butyl 1-(6-hydroxyquinolin-3-yl)pyrrolidin-3-ylcarbamate (Q1.i)

A mixture of Intermediate A (1.50 g, 5.07 mmol), tert-butylpyrrolidin-3-ylcarbamate (1.13 g, 6.09 mmol), Pd₂(dba)₃ (0.232 g, 0.254mmol), Xantphos (0.294 g, 0.507 mmol) and KO^(t)Bu (1.14 g, 10.2 mmol)in DMF (15 mL) was bubbled with argon for 20 min. The result mixture washeated at 110° C. overnight. The solution was cooled to rt and thesolvent was removed under reduced pressure. The residue was diluted withwater, extracted with DCM three times. The combined organic phase wasdried over anhydrous Na₂SO₄, filtered and concentrated. The crudeproduct was purified by chromatography (eluting with 5% MeOH in DCM) togive the title compound as yellow solid (0.2 g, yield 11%). LCMS (methodN): [M+H]⁺=330, t_(R)=1.93 min.

3-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)quinolin-6-yltrifluoromethanesulfonate (intermediate Q1)

To a suspension of Q1.i (200 mg, 0.546 mmol) in pyridine (1.5 mL) wasadded Tf₂O (0.11 mL, 0.656 mmol) dropwise under ice-bath. The reactionwas stirred at rt overnight, then quenched by saturated NaHCO₃ andconcentrated under reduced pressure. The residue was diluted with water,extracted with DCM three times. The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated. Thecrude product was purified by chromatography (eluting with 5% MeOH inDCM) to give the title compound as yellow solid (130 mg, yield 46%).LCMS (method N): [M+H]⁺=462, t_(R)=2.78 min. ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.62 (d, 1H), 7.97 (d, 1H), 7.87 (s, 1H), 7.37 (dd, 1H), 7.27 (d,1H), 7.23 (s, 1H), 4.20 (broad, 1H), 3.67-3.63 (m, 1H), 3.56˜3.54 (m,1H), 3.45˜3.43 (m, 1H), 3.26˜3.22 (m, 1H), 2.24˜2.16 (m, 1H), 1.99˜1.94(m, 1H), 1.40 (s, 9H).

Intermediate Q2 (S)-3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-yltrifluoromethanesulfonate

(S)-1-(6-(benzyloxy)quinolin-3-yl)-N,N-dimethylpyrrolidin-3-amine (Q2.i)

A mixture of Intermediate B (450 mg, 1.43 mmol),(S)—N,N-dimethylpyrrolidin-3-amine (196 mg, 1.72 mmol), Pd₂(dba)₃ (65.6mg, 0.072 mmol), Xantphos (83 mg, 0.143 mmol) and KO^(t)Bu (241 mg, 2.15mmol) in toluene (4.5 mL) was bubbled with argon for 20 min. Theresulting mixture was heated at 110° C. overnight. The solution wascooled to rt and the solvent was removed under reduced pressure. Theresidue was diluted with water, extracted with DCM three times. Thecombined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by chromatography (elutingwith 5% MeOH in DCM) to give the title compound as yellow solid (435 mg,yield 83%). LCMS (method N): [M+H]⁺=348, t_(R)=1.72 min.

(S)-3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-ol (Q2.ii)

To a solution of Q2.i (435 mg, 1.43 mmol) in MeOH (10 mL) was added 10%Pd/C (133 mg, 0.125 mmol). The mixture was reacted under hydrogenatmosphere overnight. The result mixture was filtrated. The filtrate wasconcentrated under reduced pressure, dried in vacuum to give the titlecompound as yellow solid (280 mg, yield 78%). ¹H-NMR (400 MHz, DMSO-d₆)δ ppm 9.68 (s, 1H), 8.29 (d, 1H), 7.63 (d, 1H), 6.90˜6.87 (m, 3H),3.61˜3.57 (m, 1H), 3.53˜3.49 (m, 1H), 3.38˜3.32 (m, 1H), 3.16-3.12 (m,1H), 2.83-2.79 (m, 1H), 2.22-2.16 (m, 7H), 1.85˜1.80 (m, 1H).

(S)-3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-yltrifluoromethanesulfonate (intermediate Q2)

To a suspension of Q2.ii (280 mg, 0.979 mmol) and pyridine (0.2 mL, 2.45mmol) in DCM (5 mL) was added Tf₂O (0.15 mL, 1.96 mmol) dropwise underice-bath. The reaction was stirred at rt overnight, then quenched bysaturated NaHCO₃ and concentrated under reduced pressure. The residuewas diluted with water, extracted with DCM three times. The combinedorganic phase was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product was purified bychromatography (eluting with 5% MeOH in DCM) to give the title compoundas yellow solid (130 mg, yield 46%). LCMS (method N): [M+H]⁺=390,t_(R)=2.75 min. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.65 (d, 1H), 7.97 (d,1H), 7.83 (s, 1H), 7.37 (d, 1H), 7.24 (s, 1H), 4.09˜4.06 (m, 2H), 3.66(t, 1H), 3.59 (t, 1H), 3.44˜3.38 (m, 1H), 3.24˜3.20 (m, 1H), 2.90(broad, 1H), 2.26 (s, 6H), 1.93˜1.83 (m, 1H).

Intermediate Q3 (S)-tert-butyl3-(6-(trifluoromethylsulfonyloxy)quinolin-3-ylamino)pyrrolidine-1-carboxylate

(S)-tert-butyl3-(6-(benzyloxy)quinolin-3-ylamino)pyrrolidine-1-carboxylate (Q3.i) wasprepared using the same procedure as described for Intermediate Q2.i, byusing Intermediate B and the equivalent amount of (S)-tert-butyl3-aminopyrrolidine-1-carboxylate instead of the(S)—N,N-dimethylpyrrolidin-3-amine. LCMS (method P): [M+H]⁺=420,t_(R)=1.71 min.

(S)-tert-butyl 3-(6-hydroxyquinolin-3-ylamino)pyrrolidine-1-carboxylate(Q3.ii) was prepared from Q3.i using the same procedure as described forintermediate Q2.ii. LCMS (method P): [M+H]⁺=330, t_(R)=1.64 min.

(S)-tert-butyl3-(6-(trifluoromethylsulfonyloxy)quinolin-3-ylamino)pyrrolidine-1-carboxylate(Intermediate Q3) was prepared using from Q3.ii the same procedure asdescribed for intermediate Q2. LCMS (method P): [M+H]⁺=406, t_(R)=1.76min. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 8.51 (d, 1H), 7.94 (d, 1H), 7.73(s, 1H), 7.33 (dd, 1H), 7.25 (d, 1H), 4.17 (broad, 1H), 3.77˜3.71 (m,1H), 3.56˜3.49 (m, 2H), 3.37˜3.34 (m, 1H), 2.34˜2.27 (m, 1H), 2.03˜2.00(m, 1H), 1.48 (d, 6H).

Intermediate Q4 3-((4-methylpiperazin-1-yl)methyl)quinolin-6-yltrifluoromethanesulfonate

1-((6-(benzyloxy)naphthalen-2-yl)methyl)-4-methylpiperazine (Q4.i)

A mixture of Intermediate B (500 mg, 1.60 mmol), potassiumtrifluoro[(4-methylpiperazin-1-yl)methyl]borate (351 mg, 1.60 mmol),dibromobis(tri-tert-butylphosphine)dipalladium(I) (124 mg, 0.16 mmol),and caesium carbonate (1.56 g, 4.79 mmol) in THF (5 mL)/H₂O (0.5 mL) wasbubbled with argon for 20 min. The result mixture was kept at 80° C. andstirred overnight. Then the reaction mixture was cooled to rt, water wasadded and the product was then extracted with DCM three times. Thecombined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by chromatography (elutingwith 5% MeOH in DCM) to give the title compound as yellow solid (180 mg,yield 33%). ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.74 (s, 1H), 8.00 (d, 1H),7.93 (s, 1H), 7.49˜7.35 (m, 5H), 7.13 (s, 1H), 5.19 (s, 2H), 3.67 (s,2H), 3.49 (s, 1H), 2.75˜2.40 (broad, 7H), 2.32 (s, 3H).

3-((4-methylpiperazin-1-yl)methyl)quinolin-6-ol (Q4.ii) was preparedfrom Q4.i using the same procedure as described for intermediate Q2.ii.LCMS (method N): [M+H]⁺=258, t_(R)=0.29 min.

3-((4-methylpiperazin-1-yl)methyl)quinolin-6-yltrifluoromethanesulfonate (intermediate Q4) was prepared from Q4.iiusing the same procedure as described for intermediate Q2. ¹H-NMR (400MHz, MeOH-d₄) δ ppm 8.92 (s, 1H), 8.33 (d, 1H), 8.13 (dd, 1H), 7.96 (d,1H), 7.68 (dd, 1H), 3.77 (s, 2H), 2.87˜2.71 (broad, 4H), 2.70˜2.55(broad, 4H), 2.50 (s, 3H).

Intermediate Q53-(3-(tert-butoxycarbonylamino)piperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate

tert-butyl 1-(6-(benzyloxy)quinolin-3-yl)piperidin-3-ylcarbamate (Q5.i)was prepared from Intermediate B using the same procedure as describedfor intermediate Q2.i, by using the equivalent amount of tert-butylpiperidin-3-ylcarbamate instead of the(S)—N,N-dimethylpyrrolidin-3-amine. LCMS (method P): [M+H]⁺=434,t_(R)=1.61 min.

tert-butyl 1-(6-hydroxyquinolin-3-yl)piperidin-3-ylcarbamate (Q5.ii) wasprepared from Q5.i using the same procedure as described forintermediate Q2.ii. LCMS (method P): [M+H]⁺=344, t_(R)=1.33 min.

3-(3-(tert-butoxycarbonylamino)piperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate (intermediate Q5) was prepared from Q5.iiusing the same procedure as described for intermediate Q2. LCMS (methodP): [M+H]⁺=476, t_(R)=1.80 min. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 8.82 (d,1H), 7.95 (d, 1H), 7.76 (d, 1H), 7.57 (d, 1H), 7.40 (dd, 1H), 3.85˜3.82(m, 1H), 3.70˜3.67 (m, 2H), 3.02˜2.96 (m, 1H), 2.88˜2.82 (m, 1H),1.99˜1.87 (m, 2H), 1.75˜1.71 (m, 1H), 1.51˜1.49 (m, 1H), 1.46 (s, 9H).

Intermediate Q6 3-((tetrahydrofuran-3-yl)methylamino)quinolin-6-yltrifluoromethanesulfonate

6-(benzyloxy)-N-((tetrahydrofuran-3-yl)methyl)quinolin-3-amine (Q6.i)was prepared from Intermediate B using the same procedure as describedfor intermediate Q2.i, by using the equivalent amount of(tetrahydrofuran-3-yl)methanamine instead of the(S)—N,N-dimethylpyrrolidin-3-amine. LCMS (method N): [M+H]⁺=335,t_(R)=2.32 min.

3-((tetrahydrofuran-3-yl)methylamino)quinolin-6-ol (Q6.ii) was preparedfrom Q6.i using the same procedure as described for intermediate Q2.ii.LCMS (method N): [M+H]⁺=245, t_(R)=1.40 min.

3-((tetrahydrofuran-3-yl)methylamino)quinolin-6-yltrifluoromethanesulfonate (intermediate Q6) was prepared from Q6.iiusing the same procedure as described for intermediate Q2. LCMS (methodN): [M+H]⁺=377, t_(R)=6.01 min. ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.48 (s,1H), 8.01 (d, 1H), 7.53 (s, 1H), 7.27 (d, 1H), 6.99 (s, 1H), 4.36(broad, 1H), 4.02˜3.97 (m, 1H), 3.93˜3.89 (m, 1H), 3.84˜3.78 (m, 1H),3.73˜3.70 (m, 1H), 3.26 (d, 2H), 2.67 (broad, 1H), 2.23˜2.15 (m, 1H),1.80˜1.72 (m, 1H).

Intermediate Q7 3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-6-yltrifluoromethanesulfonate

6-(6-(benzyloxy)quinolin-3-yl)-2-oxa-6-azaspiro[3.3]heptane (Q7.i) wasprepared from Intermediate B using the same procedure as described forintermediate Q2.i, by using the equivalent amount of2-oxa-6-azaspiro[3.3]heptane instead of the(S)—N,N-dimethylpyrrolidin-3-amine. LCMS (method N): [M+H]⁺=333,t_(R)=5.62 min.

3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-6-ol (Q7.ii) was preparedfrom Q7.i using the same procedure as described for intermediate Q2.ii.LCMS (method N): [M+H]⁺=242, t_(R)=1.03 min.

3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)quinolin-6-yltrifluoromethanesulfonate (intermediate Q7) was prepared from Q7.iiusing the same procedure as described for intermediate Q2. LCMS (methodN): [M+H]⁺=375, t_(R)=5.92 min.

Intermediate Q8 Trifluoro-methanesulfonic acid3-(4,4-difluoro-piperidin-1-yl)-quinolin-6-yl ester

3-(4,4-difluoropiperidin-1-yl)quinolin-6-ol (Q8.i)

A mixture of Intermediate B (879 mg, 3.30 mmol), 4,4-difluoropiperidine(400 mg, 3.30 mmol), Pd₂(dba)₃ (302 mg, 0.330 mmol), xantphos (382 mg,0.660 mmol) and KO^(t)Bu (748 mg, 6.60 mmol) in toluene (10 ml) wasbubbled with argon for 10 min. The mixture was then heated at 100° C.for overnight. The reaction was quenched with 60% NaHCO₃ aqueoussolution. The aqueous phase was extracted with DCM/IPA (20 ml×3,V/V=3/1). The combined organic phase was dried over anhydrous MgSO₄.Filtered and concentrated. The residue was purified by silica gelchromatography (eluted with 2% MeOH in DCM) to give the title compoundas yellow solid (270 mg, 31% yield). LCMS (method B): [M+H]⁺=265,t_(R)=1.79 min.

Trifluoro-methanesulfonic acid3-(4,4-difluoro-piperidin-1-yl)-quinolin-6-yl ester (intermediate Q8)

To a solution of Q8.i (270 mg, 1.022 mmol) in THF (5 ml) was added NaH(60%, 36.8 mg, 1.533 mmol) and the solution was stirred at rt for 10min. Then1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(438 mg, 1.226 mmol) was added and the reaction mixture was stirred foranother 1 h. The reaction was quenched with saturated aqueous NaHCO₃solution. The aqueous phase was extracted with DCM/IPA (20 ml×3,v/v=3:1). The combined extract was dried over anhydrous MgSO₄, filteredand concentrated. The residue was purified by silica gel chromatography(eluted with 2% MeOH in DCM) to give the title compound as yellow solid(320 mg, 79% yield). LCMS (method B): [M+H]⁺=397, t_(R)=2.68 min.

Intermediate Q9 Trifluoro-methanesulfonic acid3-(tetrahydro-pyran-4-ylamino)-quinolin-6-yl ester

Intermediate Q9 was synthesized from Intermediate A with similarprocedure as intermediate 8. LCMS (method B): [M+H]⁺=377, t_(R)=2.61min.

Intermediate Q10 3-(4-Methyl-1,4-diazepan-1-yl)quinolin-6-yltrifluoromethanesulfonate

6-(Benzyloxy)-3-(4-methyl-1,4-diazepan-1-yl)quinoline (Q10.i)

A mixture of Pd₂(dba)₃ (72.9 mg, 0.080 mmol), xantphos (101 mg, 0.175mmol), intermediate B (500 mg, 1.591 mmol), 1-methyl-1,4-diazepane (1.1)(182 mg, 1.591 mmol) and KO^(t)Bu (357 mg, 3.18 mmol) in toluene (10 ml)was bubbling with nitrogen for 15 min. The reaction was stirred at 110°C. for 3 hr under nitrogen atmosphere. The reaction mixture was filteredand concentrated. The crude product was purified by chromatography togive the title compound (320 mg, yield 58%). LCMS (method N):[M+H]⁺=348, t_(R)=1.75 min.

3-(4-Methyl-1,4-diazepan-1-yl)quinolin-6-ol (Q10.ii)

A mixture of Q10.i (310 mg, 0.892 mmol) and 10% Pd/C (18.99 mg, 0.178mmol) in MeOH (5 ml) was stirred at rt under hydrogen atmosphere forovernight. The reaction mixture was filtered and concentrated to drynessto give the title compound (220 mg, yield 96%). LCMS (method N):[M+H]⁺=258, t_(R)=0.28 min.

3-(4-Methyl-1,4-diazepan-1-yl)quinolin-6-yl trifluoromethanesulfonate(intermediate Q10)

To a solution of Q10.ii (220 mg, 0.855 mmol) in DCM (3 ml) was addedpyridine (0.41 ml, 5.13 mmol). The mixture was cooled to 0° C. and(TfO)₂O (0.36 ml, 2.138 mmol) was added dropwise. The reaction wasstirred at rt for overnight. The reaction was diluted with DCM andquenched by adding saturated NaHCO₃ aqueous. The aqueous layer wasextracted with DCM. The organic layers was combined and dried overNa₂SO₄ and concentrated. The crude product was purified bychromatography to give the title compound (260 mg, yield 74%). ¹H NMR(400 MHz, CDCl₃) δ ppm 1.39 (br, 2H) 2.13 (br, 2H) 2.45 (s, 3H) 2.65(br, 2H) 2.84 (br, 2H) 3.65 (br, 2H) 3.75 (br, 2H) 7.07 (br. s., 1H)7.51 (s, 1H) 7.99 (s, 1H) 8.72 (s, 1H), LCMS (method N): [M+H]⁺=390,t_(R)=2.69 min.

Intermediate Q11 tert-Butyl4-(6-(trifluoromethylsulfonyloxy)quinolin-3-yl)-1,4-diazepane-1-carboxylate

tert-Butyl 4-(6-(benzyloxy)quinolin-3-yl)-1,4-diazepane-1-carboxylate(Q11.i) was prepared from Intermediate B using the same procedure asdescribed for Q10.i by using the equivalent amount of tert-Butyl1,4-diazepane-1-carboxylate (2.1) instead of 1-methyl-1,4-diazepane(1.1). LCMS (method N): [M+H]⁺=434, t_(R)=2.57 min.

tert-Butyl 4-(6-hydroxyquinolin-3-yl)-1,4-diazepane-1-carboxylate(Q11.ii) was prepared from Q11.i using the same procedure as describedfor Q10.ii. LCMS (method N): [M+H]⁺=344, t_(R)=2.55 min.

tert-Butyl4-(6-(trifluoromethylsulfonyloxy)quinolin-3-yl)-1,4-diazepane-1-carboxylate(intermediate Q11) was prepared from Q11.ii using the same procedure asdescribed for intermediate Q10. LCMS (method O): [M+H]⁺=476, t_(R)=4.34min.

Intermediate Q123-(4-(tert-Butoxycarbonylamino)piperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate

tert-Butyl 1-(6-(benzyloxy)quinolin-3-yl)piperidin-4-ylcarbamate(Q12.i)was prepared from Intermediate B using the same procedure as describedfor Q10.i by using the equivalent amount of tert-Butyl1-piperidin-4-ylcarbamate (3.1) instead of 1-methyl-1,4-diazepane (1.1).LCMS (method O): [M+H]⁺=434, t_(R)=4.17 min.

tert-Butyl 1-(6-hydroxyquinolin-3-yl)piperidin-4-ylcarbamate (Q12.ii)was prepared from Q12.i using the same procedure as described forQ10.ii. LCMS (method N): [M+H]⁺=344, t_(R)=1.99 min.

3-(4-(tert-Butoxycarbonylamino)piperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate (intermediate Q12) was prepared from Q12.iiusing the same procedure as described for intermediate Q10. ¹H NMR (400MHz, CDCl₃) δ ppm 1.48 (s, 9H) 1.60-1.66 (m, 3H) 2.16 (d, 2H) 3.04 (t,2H) 3.80 (d, 2H) 7.30-7.42 (m, 2H) 7.58 (s, 1H) 8.10 (d, 1H) 8.84 (s,1H), LCMS (method O): [M+H]⁺=476, t_(R)=4.38 min.

Intermediate Q13 tert-Butyl4-(6-(trifluoromethylsulfonyloxy)quinolin-3-ylamino)piperidine-1-carboxylate

tert-Butyl 4-(6-(benzyloxy)quinolin-3-ylamino)piperidine-1-carboxylate(Q13.i) was prepared from Intermediate B using the same procedure asdescribed for Q10.i by using the equivalent amount of tert-Butyl4-aminopiperidine-1-carboxylate (4.1) instead of 1-methyl-1,4-diazepane(1.1). LCMS (method P): [M+H]⁺=434, t_(R)=1.88 min.

tert-Butyl 4-(6-hydroxyquinolin-3-ylamino)piperidine-1-carboxylate(Q13.ii) was prepared from Q13.i using the same procedure as describedfor Q13.ii. LCMS (method P): [M+H]⁺=344, t_(R)=1.36 min.

tert-Butyl4-(6-(trifluoromethylsulfonyloxy)quinolin-3-ylamino)piperidine-1-carboxylate(intermediate Q13) was prepared from Q13.i using the same procedure asdescribed for intermediate Q10. ¹H-NMR (400 MHz, MeOH-d₄) δ ppm1.29-1.45 (m, 2H) 1.48 (s, 9H) 2.07 (t, 2H) 3.05-3.07 (m, 2H) 3.60-3.65(m, 1H) 4.08 (t, 2H) 7.25-7.32 (m, 2H) 7.69 (d, 1H) 7.91 (d, 1H) 8.47(d, 1H). LCMS (method P): [M+H]⁺=476, t_(R)=1.78 min.

Intermediate Q14 3-(4-methylpiperazin-1-yl)quinolin-6-yltrifluoromethanesulfonate

Intermediate Q14 was synthesized from intermediate A and1-methyl-piperazine with similar procedure as intermediate 8. LCMS(method B): [M+H]⁺=376, t_(R)=1.90 min.

Intermediate Q15 tert-Butyl4-(6-(trifluoromethylsulfonyloxy)quinolin-3-yl)piperazine-1-carboxylate

tert-Butyl 4-(6-(benzyloxy)quinolin-3-yl)piperazine-1-carboxylate(Q15.i) was prepared from Intermediate B using the same procedure asdescribed for Q10.i by using the equivalent amount of tert-Butyl4-piperazine-1-carboxylate (6.1) instead of 1-methyl-1,4-diazepane(1.1). LCMS (method P): [M+H]⁺=420, t_(R)=1.88 min.

tert-Butyl 4-(6-hydroxyquinolin-3-yl)piperazine-1-carboxylate (Q15.ii)was prepared from Q15.i using the same procedure as described forQ10.ii. LCMS (method P): [M+H]⁺=330, t_(R)=1.57 min.

tert-Butyl4-(6-(trifluoromethylsulfonyloxy)quinolin-3-yl)piperazine-1-carboxylate(intermediate Q15) was prepared from Q15.ii using the same procedure asdescribed for intermediate Q10. ¹H NMR (400 MHz, MeOH-d₄) δ ppm 1.47 (s,9H) 3.31-3.39 (m, 4H) 3.66 (br, 4H) 7.48 (d, 1H) 7.67 (s, 1H) 7.83 (s,1H) 8.02 (s, 1H) 8.90 (s, 1H). LCMS (method P): [M+H]⁺=462, t_(R)=1.82min.

Intermediate Q16 3-(1,4′-Bipiperidin-1′-yl)quinolin-6-yltrifluoromethanesulfonate

3-(1,4′-Bipiperidin-1-yl)-6-(benzyloxy)quinoline (Q16.i) was preparedfrom Intermediate B using the same procedure as described for Q10.i byusing the equivalent amount of 1,4′-Bipiperidin (7.1) instead of1-methyl-1,4-diazepane (1.1). LCMS (method N): [M+H]⁺=402, t_(R)=1.83min.

3-(1,4′-Bipiperidin-1′-yl)quinolin-6-ol (Q16.ii) was prepared from Q16.iusing the same procedure as described for Q10.ii. LCMS (method N):[M+H]⁺=312, t_(R)=0.89 min.

3-(1,4′-Bipiperidin-1′-yl)quinolin-6-yl trifluoromethanesulfonate(intermediate Q16) was prepared from Q16.ii using the same procedure asdescribed for intermediate Q10. LCMS (method N): [M+H]⁺=444, t_(R)=1.94min.

Intermediate Q17 3-(4-Cyclohexylpiperazin-1-yl)quinolin-6-yltrifluoromethanesulfonate

6-(Benzyloxy)-3-(4-cyclohexylpiperazin-1-yl)quinoline (Q17.i) wasprepared from Intermediate B using the same procedure as described forQ10.i by using the equivalent amount of 1-cyclohexylpiperazin (8.1)instead of 1-methyl-1,4-diazepane (1.1). LCMS (method N): [M+H]⁺=402,t_(R)=1.94 min.

3-(4-Cyclohexylpiperazin-1-yl)quinolin-6-ol (Q17.ii) was prepared fromQ17.i using the same procedure as described for Q10.ii. LCMS (method N):[M+H]⁺=312, t_(R)=1.25 min.

3-(4-Cyclohexylpiperazin-1-yl)quinolin-6-yl trifluoromethanesulfonate(intermediate Q17) was prepared from Q17.ii using the same procedure asdescribed for intermediate Q10. LCMS (method N): [M+H]⁺=444, t_(R)=1.97min.

Intermediate Q18 3-(4-(Pyrrolidin-1-yl)piperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate

6-(Benzyloxy)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)quinoline (Q18.i) wasprepared from Intermediate B using the same procedure as described forQ10.i by using the equivalent amount of 4-(pyrrolidin-1-yl)piperidin(9.1) instead of 1-methyl-1,4-diazepane (1.1). LCMS (method N):[M+H]⁺=388, t_(R)=1.86 min.

3-(4-(Pyrrolidin-1-yl)piperidin-1-yl)quinolin-6-ol (Q18.ii) was preparedfrom Q18.i using the same procedure as described for Q10.ii. LCMS(method N): [M+H]⁺=298, t_(R)=0.37 min.

3-(4-(Pyrrolidin-1-yl)piperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate (intermediate Q18) was prepared from Q18.iiusing the same procedure as described for intermediate Q10. LCMS (methodN): [M+H]⁺=430, t_(R)=1.83 min.

Intermediate Q19 3-(4-Phenylpiperazin-1-yl)quinolin-6-yltrifluoromethanesulfonate

6-(Benzyloxy)-3-(4-phenylpiperazin-1-yl)quinoline (Q19.i) was preparedfrom Intermediate B using the same procedure as described for Q10.i byusing the equivalent amount of 1-phenyl-piperazine (10.1) instead of1-methyl-1,4-diazepane (1.1). LCMS (method N): [M+H]⁺=396, t_(R)=2.88min.

3-(4-Phenylpiperazin-1-yl)quinolin-6-ol (Q19.ii) was prepared from Q19.iusing the same procedure as described for Q10.ii. LCMS (method N):[M+H]⁺=306, t_(R)=2.09 min.

3-(4-Phenylpiperazin-1-yl)quinolin-6-yl trifluoromethanesulfonate(intermediate Q19) was prepared from Q19.ii using the same procedure asdescribed for intermediate Q10. LCMS (method N): [M+H]⁺=438, t_(R)=2.90min.

Intermediate Q20 3-(2-Methylmorpholino)quinolin-6-yltrifluoromethanesulfonate

4-(6-(Benzyloxy)quinolin-3-yl)-2-methylmorpholine (Q20.i) was preparedfrom Intermediate B using the same procedure as described for Q10.i byusing the equivalent amount of 2-methylmorpholine (11.1) instead of1-methyl-1,4-diazepane (1.1). LCMS (method N): [M+H]⁺=335, t_(R)=2.59min.

3-(2-Methylmorpholino)quinolin-6-ol (Q20.ii) was prepared from Q20.iusing the same procedure as described for Q20.ii. LCMS (method N):[M+H]⁺=245, t_(R)=1.51 min.

3-(2-Methylmorpholino)quinolin-6-yl trifluoromethanesulfonate(intermediate Q20) was prepared from Q20.ii using the same procedure asdescribed for intermediate Q10. LCMS (method N): [M+H]⁺=377, t_(R)=2.65min.

Intermediate Q21 3-(2,6-Dimethylmorpholino)quinolin-6-yltrifluoromethanesulfonate

4-(6-(Benzyloxy)quinolin-3-yl)-2,6-dimethylmorpholine (Q21.i) wasprepared from Intermediate B using the same procedure as described forQ10.i by using the equivalent amount of 2,6-dimethylmorpholine (12.1)instead of 1-methyl-1,4-diazepane (1.1). LCMS (method N): [M+H]⁺=349,t_(R)=2.68 min.

3-(2,6-Dimethylmorpholino)quinolin-6-ol (Q21.ii) was prepared from Q21.iusing the same procedure as described for Q10.ii. LCMS (method N):[M+H]⁺=259, t_(R)=1.40 min.

3-(2,6-Dimethylmorpholino)quinolin-6-yl trifluoromethanesulfonate(intermediate Q21) was prepared from Q21.ii using the same procedure asdescribed for intermediate Q10. LCMS (method N): [M+H]⁺=391, t_(R)=2.72min.

Intermediate Q22 (2S,6R)-tert-Butyl2,6-dimethyl-4-(6-(trifluoromethylsulfonyloxy)quinolin-3-yl)piperazine-1-carboxylate

tert-Butyl4-(6-(benzyloxy)quinolin-3-yl)-2,6-dimethylpiperazine-1-carboxylate(Q22.i) was prepared from Intermediate B using the same procedure asdescribed for Q10.i by using the equivalent amount of (2S,6R)-tert-Butyl2,6-dimethylpiperazine-1-carboxylate (13.1) instead of1-methyl-1,4-diazepane (1.1). LCMS (method N): [M+H]⁺=448, t_(R)=2.96min.

tert-Butyl4-(6-hydroxyquinolin-3-yl)-2,6-dimethylpiperazine-1-carboxylate (Q22.ii)was prepared from Q22.i using the same procedure as described forQ10.ii. LCMS (method N): [M+H]⁺=358, t_(R)=1.27 min.

(2S,6R)-tert-Butyl2,6-dimethyl-4-(6-(trifluoromethylsulfonyloxy)quinolin-3-yl)piperazine-1-carboxylate (intermediate Q22) was prepared from Q22.iiusing the same procedure as described for intermediate Q10. LCMS (methodN): [M+H]⁺=490, t_(R)=2.96 min.

Intermediate Q23 3-(4-Methoxypiperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate

6-(Benzyloxy)-3-(4-methoxypiperidin-1-yl)quinoline (Q23.i) was preparedfrom Intermediate B using the same procedure as described for Q10.i byusing the equivalent amount of 4-methoxypiperidin (14.1) instead of1-methyl-1,4-diazepane (1.1). LCMS (method N): [M+H]⁺=349, t_(R)=2.54min.

3-(4-Methoxypiperidin-1-yl)quinolin-6-ol (Q23.ii) was prepared fromQ23.i using the same procedure as described for Q10.ii. LCMS (method N):[M+H]⁺=259, t_(R)=1.58 min.

3-(4-Methoxypiperidin-1-yl)quinolin-6-yl trifluoromethanesulfonate(intermediate Q23) was prepared from Q23.ii using the same procedure asdescribed for intermediate Q10. LCMS (method N): [M+H]⁺=391, t_(R)=2.66min.

Intermediate Q24 (S)-tert-Butyl3-methyl-4-(6-(trifluoromethylsulfonyloxy)quinolin-3-yl)piperazine-1-carboxylate

(S)-tert-Butyl4-(6-(benzyloxy)quinolin-3-yl)-3-methylpiperazine-1-carboxylate (Q24.i)was prepared from Intermediate B using the same procedure as describedfor Q10.i by using the equivalent amount of (S)-tert-Butyl3-methylpiperazine-1-carboxylate (15.1) instead of1-methyl-1,4-diazepane (1.1). LCMS (method N): [M+H]⁺=434, t_(R)=2.81min.

(S)-tert-Butyl4-(6-hydroxyquinolin-3-yl)-3-methylpiperazine-1-carboxylate (Q24.ii) wasprepared from Q24.i using the same procedure as described for Q10.ii.LCMS (method N): [M+H]⁺=344, t_(R)=1.28 min.

(S)-tert-Butyl3-methyl-4-(6-(trifluoromethylsulfonyloxy)quinolin-3-yl)piperazine-1-carboxylate(intermediate Q24) was prepared from Q24.ii using the same procedure asdescribed for intermediate Q10. LCMS (method N): [M+H]⁺=476, t_(R)=2.79min.

Intermediate Q25 Trifluoro-methanesulfonic acid3-(8-oxa-2-aza-spiro[4.5]dec-2-yl)-quinolin-6-yl ester

6-Benzyloxy-3-(8-oxa-2-aza-spiro[4.5]dec-2-yl)-quinoline (Q25.i) wasprepared from Intermediate B using the same procedure as described forQ10.i by using the equivalent amount of 8-oxa-2-aza-spiro[4.5]decan(16.1) instead of 1-methyl-1,4-diazepane (1.1). LCMS (method A):[M+H]⁺=375, t_(R)=2.47 min.

3-(8-Oxa-2-aza-spiro[4.5]dec-2-yl)-quinolin-6-ol (Q25.ii) was preparedfrom Q25.i using the same procedure as described for Q10.ii. LCMS(method A): [M+H]⁺=285, t_(R)=4.90 min.

Trifluoro-methanesulfonic acid3-(8-oxa-2-aza-spiro[4.5]dec-2-yl)-quinolin-6-yl ester (intermediateQ25) was prepared from Q25.ii using the same procedure as described forintermediate Q10. LCMS (method A): [M+H]⁺=417, t_(R)=2.73 min.

Intermediate Q26

Trifluoro-methanesulfonic acid3-(tetrahydro-furan-3-ylamino)-quinolin-6-yl ester

(6-Benzyloxy-quinolin-3-yl)-(tetrahydro-furan-3-yl)-amine (Q26.i) wasprepared from Intermediate B using the same procedure as described forQ10.i by using the equivalent amount of 3-Amino-tetrahydro-furan (17.1)instead of 1-methyl-1,4-diazepane (1.1). LCMS (method A): [M+H]⁺=321,t_(R)=2.38 min.

3-(Tetrahydro-furan-3-ylamino)-quinolin-6-ol (Q26.ii) was prepared fromQ26.i using the same procedure as described for Q10.ii. LCMS (method A):[M+H]⁺=231, t_(R)=1.58 min.

Trifluoro-methanesulfonic acid3-(tetrahydro-furan-3-ylamino)-quinolin-6-yl ester (intermediate Q26)was prepared from Q26.ii using the same procedure as described forintermediate Q10. LCMS (method A): [M+H]⁺=363, t_(R)=2.54 min.

Intermediate Q273-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate

6-(benzyloxy)-3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)quinoline(Q27.i) was prepared from Intermediate B using the same procedure asdescribed for Q10.i by using the equivalent amount of1-((tert-butyldimethylsilyl)oxy)piperidin (18.1) instead of1-methyl-1,4-diazepane (1.1). LCMS (method M): [M+H]⁺=449, t_(R)=2.46min.

3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)quinolin-6-ol (Q27.ii)was prepared from Q27.i using the same procedure as described forQ10.ii. LCMS (method N): [M+H]⁺=359, t_(R)=2.81 min.

3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate (intermediate Q27) was prepared from Q27.iiusing the same procedure as described for intermediate Q10. ¹H-NMR (400MHz, CDCl₃) δ ppm 8.68 (s, 1H), 7.89 (d, 1H), 7.21 (d, 1H), 7.11 (dd,1H), 7.01 (s, 1H), 3.91˜3.98 (m, 1H), 3.49-3.59 (m, 2H), 3.12-3.20 (m,2H), 1.88-1.98 (m, 2H), 1.68-1.78 (m, 2H), 0.92 (s, 9H), 0.10 (s, 6H).

Intermediate Q283-(2-(tert-butyldimethylsilyloxy)ethylamino)quinolin-6-yltrifluoromethanesulfonate

6-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)quinolin-3-amine(Q28.i)

To a suspension of Intermediate B (4.0 g, 12.73 mmol) in toluene (90ml), 2-(tert-butyl-dimethyl-silanyloxy)-ethylamine (6.70 g, 38.2 mmol),KO^(t)Bu (0.714 g, 6.37 mmol), xantphos (1.473 g, 2.55 mmol) andPd₂(dba)₃ (0.291 g, 0.318 mmol) were added under N₂ atmosphere. Thereaction was stirred at 100° C. for 8 h. After being cooled to rt, themixture was concentrated under reduced pressure. The residue was thendissolved in 200 ml of EtOAc, washed with water (30 ml) and brine (30ml). The organic phase was dried over Na₂SO₄, then filtered andconcentrated to afford the crude product, which was purified by silicagel chromatography (DCM/MeOH=30/1) to afford the title compound as brownoil (3.6 g, 40.1% yield). LCMS (method B): [M+H]⁺=409, t_(R)=3.21 min.

3-(2-(tert-buty Idimethylsilyloxy)ethylamino)quinolin-6-ol (Q28.ii)

To a solution of Q28.i (4.0 g, 9.79 mmol) in MeOH (200 ml), 10%palladium on carbon (1.042 g, 0.979 mmol) was added. After being stirredunder H₂ atmosphere at 25° C. for 3 h, the reaction mixture was filteredthrough celite and concentrated under reduced pressure to afford thetitle compound as pale yellow oil (2.5 g, 39.3% yield). The crudeproduct was used without further purification. LCMS (method B):[M+H]⁺=319, t_(R)=2.42 min.

3-(2-(tert-buty Idimethylsilyloxy)ethylamino)quinolin-6-yltrifluoromethanesulfonate (Intermediate Q28)

To a solution of Q28.ii (2.3 g, 7.22 mmol) in DCM (200 ml) was addedpyridine (1.168 ml, 14.44 mmol). The mixture was cooled to 0° C., andtrifluoromethanesulfonic anhydride (3.06 g, 10.83 mmol) was then addedin dropwise. The reaction was allowed to warm to rt and stirred for 2 h.The reaction solvent was removed under reduced pressure and the residuewas dissolved in DCM (50 ml), washed with water (10 ml) and brine (10ml). The organic phase was then dried over anhydrous Na₂SO₄, filteredand concentrated to give the crude product, which was purified by silicagel chromatography (DCM/MeOH=30/1) to afford the title compound as brownoil (1.5 g, 17.06% yield). LCMS (method B): [M+H]⁺=450, t_(R)=3.33 min.

Intermediate Q29 3-(tert-butoxycarbonylamino)quinolin-6-yltrifluoromethanesulfonate

Intermediate B (4.0 g, 12.73 mmol), benzylamine (4.09 g, 38.2 mmol),xantphos (1.473 g, 2.55 mmol), KO^(t)Bu (2.86 g, 25.5 mmol) andPd₂(dba)₃ (1.166 g, 1.273 mmol) were suspended in toluene (90 ml). Themixture was bubbled with N₂ for 10 min and stirred at 100° C. for 8 h.The reaction was cooled and concentrated under reduced pressure. Theresidue was dissolved in 100 ml of EtOAc, washed with water (20 ml) andbrine (20 ml). The organic phase was dried over Na₂SO₄, filtered andconcentrated to afford the crude desired product, which was purified bysilica gel chromatography (DCM/MeOH=30/1) to afford the title compoundas pale yellow solid (4.0 g, 72.0% yield). LCMS (method B): [M+H]⁺=341,t_(R)=2.76 min.

3-aminoquinolin-6-ol (Q29.ii) was obtained by adding to a solution ofQ29.i (1.0 g, 2.94 mmol) in MeOH (10 ml), 10% Palladium on carbon (0.313g, 0.294 mmol), and stirring the reaction mixture under H₂ atmosphere (1atm) at 60° C. for 8 h. The reaction mixture was filtered throughcelite, and the filtrate was concentrated under reduced pressure toafford the title compound as pale yellow solid (0.5 g, 80% yield). Thecrude product was used without further purification. LCMS (method B):[M+H]⁺=161, t_(R)=0.31 min.

tert-butyl 6-hydroxyquinolin-3-ylcarbamate (Q29.iii)

To a solution of Q29.ii (0.5 g, 3.12 mmol) in THF (10 ml), (Boc)₂O(1.450 ml, 6.24 mmol) was added, and the reaction mixture was stirred atreflux for 24 h. THF was removed under reduced pressure. The residue wasdissolved in EtOAc (50 ml), subsequently washed with 1% HCl solution (10ml), water (10 ml), sat. 60% NaHCO₃ (10 ml) and brine (10 ml). Theorganic phase was dried over MgSO₄, filtered and concentrated to affordthe crude product as brown oil, which was purified by silica gelchromatography (DCM/MeOH=30/1) to afford the title compound as whitesolid (0.5 g, 61.5% yield). LCMS (method B): [M+H]⁺=261, t_(R)=2.17 min.

3-(tert-butoxycarbonylamino)quinolin-6-yl trifluoromethanesulfonate(Intermediate Q29)

To a solution of Q29.iii (0.3 g, 1.153 mmol) in THF (10 ml), NaH (60%,0.055 g, 2.305 mmol) was added. After stirring at rt for 30 min,1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)-methanesulfonamide(0.494 g, 1.383 mmol) was then added, and the mixture was stirred at rtfor 3 h. The reaction was then quenched with 1 ml of water and extractedwith DCM (10 ml×4). The combined organic phase was washed with 10 ml ofwater and 10 ml of brine successively. The organic phase was dried overNa₂SO₄, then filtered and concentrated to afford the crude product,which was purified by silica gel chromatography (DCM/MeOH=40/1) toafford the title compound as white solid (0.3 g, 66.3% yield). LCMS(method B): [M+H]⁺=393, t_(R)=2.79 min.

Intermediate Q30 3-(3-methylmorpholino)quinolin-6-yltrifluoromethanesulfonate

4-(6-(benzyloxy)quinolin-3-yl)-3-methylmorpholine (Q30.i)

A mixture of Intermediate B (1.0 g, 3.18 mmol), 3-methylmorpholine(0.966 g, 9.55 mmol), Pd₂(dba)₃ (0.291 g, 0.318 mmol), xantphos (0.368g, 0.637 mmol) and KO^(t)Bu (0.714 g, 6.37 mmol) in toluene (30 ml) wasbubbled with argon for 10 min. The reaction was stirred at 100° C. for 8h, cooled and concentrated under reduced pressure. The residue wasdissolved in 50 ml of EtOAc, washed with water and brine. The organicphase was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by silica gel chromatography (DCM/MeOH=30/1) to afford thetitle compound as pale yellow solid (800 mg, 60.9% yield). LCMS (methodB): [M+H]⁺=335, t_(R)=2.53 min.

3-(3-methylmorpholino)quinolin-6-ol (Q30.ii)

To a solution of Q30.i (800 mg, 2.392 mmol) in methanol (200 ml) wasadded 10% Palladium on carbon (255 mg, 0.239 mmol), and the reactionmixture was stirred under H₂ atmosphere (1 atm) at rt for 3 h. The Pd/Cwas filtered off over celite and the filtrate was concentrated to affordthe title compound (600 mg, 73.9% yield) as pale yellow solid. The crudeproduct was used without further purification. LCMS (method B):[M+H]⁺=245, t_(R)=1.42 min.

3-(3-methylmorpholino)quinolin-6-yl trifluoromethanesulfonate(Intermediate Q30)

To a solution of Q30.ii (200 mg, 0.819 mmol) in THF (10 ml), was addedNaH (60%, 65.5 mg, 1.637 mmol). After stirred at rt for 30 min,1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)-methanesulfonamide(585 mg, 1.637 mmol) was added, and the mixture was stirred at rt for 3h. Water was added (1 mL) and the mixture was extracted with DCM (10ml×4), the combined organic phase was washed with water, brine, driedover Na₂SO₄, filtered and concentrated to afford the crude product. Thecrude product was purified by silica gel chromatography (DCM/MeOH=40/1)to afford the title compound as brown oil (100 mg, 32.5% yield). LCMS(method B): [M+H]⁺=377, t_(R)=2.62 min.

Intermediate Q31 3-(2,2,6,6-tetramethylpiperidin-4-ylamino)quinolin-6-yltrifluoromethanesulfonate

The title compound was prepared starting from Intermediate B using thesame procedure as described for intermediate Q30. LCMS (method B):[M+H]⁺=432, t_(R)=2.03 min.

Intermediate Q32 3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yltrifluoromethanesulfonate

3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-ol (Q32.i)

A mixture of Intermediate A (1.8 g, 6.76 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.548 g, 7.44 mmol), Na₂CO₃ (2.151 g, 20.29 mmol) and Pd(PPh₃)₄ (0.782g, 0.676 mmol) in DMF (10 ml) was bubbled with argon for 10 min. Thenthe mixture was heated at 90° C. for 5 h. After being cooled to rt, themixture was diluted with EtOAc (40 ml), washed with water and brine,dried over Na₂SO₄, filtered and concentrated. The residue wasrecrystallized from EtOAc to afford the title compound as pale graysolid (1.1 g, 65% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.97 (s, 1H),8.91 (s, 1H), 8.33 (s, 1H), 8.23 (d, 2H), 8.00 (s, 1H), 7.80 (d, 1H),7.22 (dd, 1H), 7.00 (d, 1H), 3.90 (s, 3H). LCMS (method B): [M+H]⁺=226,t_(R)=1.41 min.

3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl trifluoromethanesulfonate(Intermediate Q32)

Q32.i (0.9 g, 4.00 mmol) was dissolved in pyridine (8 ml). The solutionwas cooled to 0° C. and trifluoromethanesulfonic anhydride (1.353 g,4.79 mmol) was added. The reaction was allowed to warm up to rt andstirred at rt for 10 h. The reaction was then quenched with saturatedNaHCO₃ and extracted with DCM (20 ml×3). The combined organic phase waswashed with water, brine, dried over Na₂SO₄ and concentrated. Theresidue was recrystallized from EtOAc to afford the title compound asgray solid. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.30 (s, 1H), 8.61 (s, 1H),8.42 (s, 1H), 8.17 (d, 1H), 8.10 (t, 2H), 7.76 (dd, 1H), 3.92 (s, 3H).LCMS (method B): [M+H]+=358, t_(R)=2.43 min.

Intermediate Q33 3-morpholinoquinolin-6-yl trifluoromethanesulfonate

3-Morpholin-4-ylquinolin-6-ol (Q33.i)

A mixture of Intermediate A (0.8 g, 3.01 mmol), morpholine (1.048 g,12.03 mmol), Pd₂(dba)₃ (0.275 g, 0.301 mmol), xantphos (0.305 g, 0.602mmol) and KO^(t)Bu (0.337 g, 3.01 mmol) in toluene (15 ml) was bubbledwith N₂ for 15 min and then was heated at 100° C. for 5 h under MWradiation. The mixture was quenched with saturated aqueous NaHCO₃solution. The aqueous phase was extracted with DCM/IPA (10 ml, v/v=3/1)for 3 times. The combined extract was dried over anhydrous MgSO₄.Filtered and concentrated, the residue was purified by silica gelchromatography to afford the title compound (0.31 g, 40.3% yield). LCMS(method B): [M+H]⁺=231, t_(R)=1.1 min.

3-morpholin-4-ylquinolin-6-yl trifluoromethanesulfonate (IntermediateQ33)

To a solution of Q33.i (300 mg, 1.303 mmol) in pyridine (5 ml) was addedTf₂O (441 mg, 1.563 mmol) at 0° C. The mixture was then stirred at rtfor 20 h. The reaction was quenched with 60% NaHCO₃ aqueous solution andthe aqueous phase was extracted with DCM (20 ml×3). The combined extractwas washed with water, dried over anhydrous MgSO₄, filtered andconcentrated to afford the title compound as brown solid (0.22 g, 37.3%yield), which was used directly in the next step. LCMS (method B):[M+H]⁺=363, t_(R)=2.49 min.

Alternatively, Intermediate Q33 can by prepared according to theprocedure described for Intermediates Q10 and Q28 starting fromIntermediate B, via 6-benzyloxy-3-morpholin-4-yl-quinol (Q33.ii)

Intermediate Q34 Trifluoro-methanesulfonic acid3-(1-methyl-piperidin-4-ylamino)-quinolin-6-yl ester

6-Benzyloxy-quinolin-3-yl-(1-methyl-piperidin-4-yl)-amine (Q34.i) wasprepared from Intermediate B and 4-amino-1-methylpiperidine using thesame procedure as described for Q10.i. LCMS (method O): [M+H]⁺=248,t_(R)=1.38 min.

3-(1-Methyl-piperidin-4-ylamino)-quinolin-6-ol (Q34.ii) was preparedfrom Q34.i using the same procedure as described for Q10.ii. LCMS(method O): [M+H]⁺=258, t_(R)=0.92 min.

3-(4-(tert-Butoxycarbonylamino)piperidin-1-yl)quinolin-6-yltrifluoromethanesulfonate (intermediate Q34) was prepared from Q34.iiusing the same procedure as described for intermediate Q10. LCMS (methodO): [M+H]⁺=390, t_(R)=1.35 min. ¹H NMR (400 MHz, MeOH-d₄) δ ppm 8.49 (d,1H), 7.92 (d, 1H), 7.69 (d, 1 h), 7.31 (dd, 1H), 7.27 (d, 1H), 3.62 (m,1H), 3.28 (m, 2H), 2.86 (m, 2H), 2.65 (s, 3H), 2.26 (m, 2H), 1.75 (m,2H).

Intermediate Q35 3-(morpholinomethyl)quinolin-6-yltrifluoromethanesulfonate

3-(morpholinomethyl)quinolin-6-ol (Q35.i)

A mixture of Cs₂CO₃ (4.75 g, 14.49 mmol), Intermediate A (1.285 g, 4.83mmol) and trifluoroborate salts (1 g, 4.83 mmol) in THF (15 ml) wasbubbled with N₂ for 10 min. Then Pd(OAc)₂ (0.033 g, 0.145 mmol) wasadded. The mixture was stirred at 80° C. for 20 h. The mixture wasdiluted with water, the organic phase was separated and the aqueousphase was concentrated and dried on vacuum to afford the title compoundas yellow solid The solid was used in the next step without furtherpurification (440 mg, 33.6% yield). LCMS (method B): [M+H]⁺=245,t_(R)=0.44 min.

3-(morpholinomethyl)quinolin-6-yl trifluoromethanesulfonate(Intermediate Q35)

To a solution of 3-(morpholinomethyl)quinolin-6-ol (400 mg, 1.637 mmol)in pyridine (5 ml) was added trifluoromethanesulfonic anhydride (462 mg,1.637 mmol) and the mixture was stirred at rt for 8 h. The reaction wasquenched with saturated aqueous NaHCO₃ solution. The aqueous phase wasextracted with DCM for 3 times The extract was washed with water andbrine. The organic phase was dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatography toafford the title compound as yellow oil (110 mg, 16.1% yield). LCMS(method B): [M+H]⁺=377, t_(R)=1.78 min.

Intermediate Q36 3-(oxetan-3-ylamino)quinolin-6-yltrifluoromethanesulfonate

The title compound was prepared from Intermediate B and 3-aminooxetaneusing the same procedure as described for intermediate Q30. LCMS (methodB): [M+H]⁺=349, t_(R)=2.50 min.

SYNTHESES OF EXAMPLES

The following section describes the synthesis of examples in detail. Thecharacterizing data for these compounds as well as for other examplessynthesized by similar methods are given in the table below.

Example 1 Synthesis Method 1A tert-butyl1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-ylcarbamate

A mixture of Intermediate E (10 mg, 0.043 mmol), Intermediate Q1 (20 mg,0.043 mmol), Pd₂(dba)₃ (1.94 mg, 2.17 μmol), Xantphos (2.51 mg, 4.33μmol) and DIPEA (0.015 mL, 0.087 mmol) in DMF (0.5 mL) was bubbled withArgon for 20 min. The result mixture was heated at 100° C. overnight,then cooled to rt, filtrated and the filtrate was concentrated underreduced pressure. The residue was purified by prep-HPLC to give thetitle compound as yellow solid (15 mg, yield 57%). [Method 1A]

Example 2 Synthesis Method 1B1-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-amine

To a solution of Example 1 (14 mg, 0.026 mmol) in DCM (2.0 mL) was addedTFA (0.5 mL) dropwise under ice-bath. The mixture was stirred at rt for2 hours, then based with saturated NaHCO₃. The result solution wasconcentrated under reduced pressure. The residue was purified byprep-HPLC to give the title compound as yellow solid (9 mg, yield 71%).[Method 1B]

Example 7 Method 26-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(2,2,6,6-tetramethylpiperidin-4-yl)quinolin-3-amine

A mixture of Intermediate Q31 (100 mg, 0.232 mmol), Intermediate F (57.8mg, 0.232 mmol), Pd₂(dba)₃ (21.22 mg, 0.023 mmol), xantphos (26.8 mg,0.046 mmol) and DIPEA (0.081 ml, 0.464 mmol) in DMF (5 ml) was bubbledwith Argon gas for 10 min, then the reaction tube was sealed and heatedat 100° C. for 1 h under MW radiation. The solvent was removed underreduced pressure. The residue was purified by prep-HPLC to afford thetitle compound as pale yellow solid (60 mg, 48.8% yield). [Method 2]

Example 16 Reference Compound6-[6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-3-(pyrrolidin-3-yloxy)-quinoline

tert-butyl 3-(6-bromoquinolin-3-yloxy)pyrrolidine-1-carboxylate (16.1)

To a solution of 6-bromoquinolin-3-ol (500 mg, 2.232 mmol), tert-butyl3-hydroxypyrrolidine-1-carboxylate (418 mg, 2.232 mmol) and triphosphine(875 mg, 3.35 mmol) in THF (10 ml) was added DEAD (0.424 ml, 2.68 mmol)at 0° C. Then the mixture was stirred at 50° C. for 6 h under N₂. Themixture was diluted with ether and filtered. The filtrate wasconcentrated. The residue was purified by silica gel chromatographyeluted with Hex/EA (from 100% to 95%) to afford the title compound (650mg, 67% yield) as brown gel.

3-{6-[6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yloxy}-pyrrolidine-1-carboxylicacid tert-butyl ester (16.2) was synthesized using the same procedure asexample 1 (method 1A). (68 mg, 41% yield). ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.98 (s, 1H), 8.54 (s, 1H), 8.31 (s, 1H), 7.97 (m, 3H), 7.81 (d,1H), 7.53 (s, 1H), 7.16 (d, 1H), 7.07 (s, 1H), 5.47 (m, 1H), 3.83 (s,3H), 3.55 (m, 1H), 3.14 (m, 3H), 2.20 (m, 2H), 1.34 (s, 9H). LCMS(method B): [M+H]⁺=544, t_(R)=2.20 min.

6-[6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-3-(pyrrolidin-3-yloxy)-quinoline(example 16) was obtained by stirring a solution of 16.2 (40 mg, 0.074mmol) in MeOH (contains 10% HCl) at rt for about 2 h. The solvent wasremoved and the residue was purified by prep-HPLC to give white solid(20 mg, 61% yield) as the title compound. ¹H-NMR (400 MHz, DMSO-d₆) δppm 8.96 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.99 (m, 2H), 7.93 (d,1H), 7.82 (d, 1H), 7.55 (s, 1H), 7.13 (d, 1H), 7.00 (s, 1H), 5.31 (m,1H), 3.83 (s, 3H), 3.06 (m, 1H), 2.90 (m, 2H), 2.83 (m, 2H), 2.02 (m,1H), 1.75 (m, 1H). LCMS (method B): [M+H]⁺=444, t_(R)=1.69 min.

Example 28 Method 1C6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinoline

A suspension of6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(piperazin-1-yl)quinoline(Example 27—see in Table below) (12 mg, 0.027 mmol),1,1,1-trifluoro-2-iodoethane (56.9 mg, 0.271 mmol) and DIPEA (17.5 mg,0.136 mmol) in DMF (1 mL) was sealed in a microwave vial and heated at120° C. for 6 hours. The solvent was removed and the residue waspurified by prep-HPLC to give the title compound as yellow solid (3 mg,yield 20%). [Method 1C]

Example 29 Method 1D2-(4-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-1,4-diazepan-1-yl)ethanol

A mixture of3-(1,4-Diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline(Example 19—see in Table below) (15 mg, 0.033 mmol), 2-bromoethanol(12.33 mg, 0.099 mmol) and K₂CO₃ (9.08 mg, 0.066 mmol) in DMF (0.5 ml)was stirred at rt for 24 hr. The mixture was purified by prep-HPLC togive the title compound (6 mg, yield 36%). [Method 1D]

Example 491-(6-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol

3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinoline(49.1)

The title compound was prepared using the same procedure as described inthe synthesis of example 1 starting from Intermediate Q27 andIntermediate E. LCMS (method B): [M+H]⁺=571, t_(R)=3.20.

1-(6-((6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-ol(Example 49) (Method 1E)

To a solution of (49.1) (48.5 mg, 0.085 mmol) in MeOH (2 mL) was addedHCl solution in MeOH (1M) (5 mL, 5.00 mmol). The reaction mixture wasstirred at rt for 1 h, quenched with saturated NaHCO₃ solution andextracted with extracted with CH₂Cl₂. The combined organic layers weredried over anhydrous Na₂SO₄, concentrated, purified via biotage by flashchromatography on silica gel using a gradient of 0-10% MeOH/CH₂Cl₂ togive the title compound (38 mg, 0.083 mmol, 98% yield). [Method 1E]

Example 53 Method 3)2-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)ethanol

N-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-amine(53.1)

A mixture of Intermediate Q28 (0.2 g, 0.444 mmol), Intermediate E (0.103g, 0.444 mmol), xantphos (0.051 g, 0.089 mmol), Pd₂(dba)₃ (0.041 g,0.044 mmol) and DIPEA (0.155 ml, 0.888 mmol) in DMF (10 ml) was bubbledwith Ar gas for 10 min and then the reaction mixture was stirred underMW radiation at 110° C. for 1 h. The solvent was removed under reducedpressure. The residue was purified by silica gel chromatography(DCM/MeOH=40/1) to afford the title compound as brown oil (0.1 g, 42.4%yield). LCMS (method B): [M+H]⁺=532, t_(R)=2.74 min.

2-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylamino)ethanol(Example 53)

To a solution of (53.1) (100 mg, 0.188 mmol) in THF (10 ml), TBAF (98mg, 0.376 mmol) was added. The reaction mixture was stirred at rt for 3h. The solvent was then removed under reduced pressure. The residue wasdissolved in 30 ml of DCM, washed with water (10 ml×3) and brine (10 ml)successively. The organic phase was dried over Na₂SO₄, then filtered andconcentrated. The residue was purified by silica gel chromatography(DCM/MeOH=10/1) to afford the title compound as pale yellow solid (22mg, 28% yield). [Method 3]

Example 55 Method 46-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-aminehydrochloride

Tert-butyl6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-ylcarbamate(55.1)

A mixture of Intermediate Q29 (0.2 g, 0.510 mmol), Intermediate F (0.127g, 0.510 mmol), Pd₂(dba)₃ (0.047 g, 0.051 mmol), xantphos (0.059 g,0.102 mmol) and DIPEA (0.178 ml, 1.019 mmol) in DMF (10 ml) was bubbledwith Ar gas for 10 min, and the reaction tube was sealed and heated at110° C. for 1 h under MW radiation. The solvent was removed underreduced pressure. The residue was purified by silica gel chromatography(DCM/MeOH=40/1) to afford the title product as brown oil (0.12 g, 47.9%yield). LCMS (method B): [M+H]⁺=492, t_(R)=2.52 min.

6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-aminehydrochloride (Example 55)

(55.1) (0.12 g, 0.244 mmol) was dissolved in HCl solution (4 M in MeOH,20 ml, 0.08 mol), and the reaction mixture was stirred at rt for 2 h.The solvent was removed under reduced pressure to afford the titleproduct as yellow solid (60 mg, 62.8% yield). [Method 4]

Example 57 Method 54-(6-(8-fluoro-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine

A mixture of Intermediate C (100 mg, 0.460 mmol), Intermediate Q33 (167mg, 0.460 mmol), xantphos (53.3 mg, 0.092 mmol), Pd₂(dba)₃ (42.2 mg,0.046 mmol), DIPEA (0.161 ml, 0.921 mmol) in DMF (10 ml) was bubbledwith Argon gas for 10 min, then the reaction tube was sealed and heatedat 110° C. for 1 h under MW radiation. The solvent was removed underreduced pressure. The residue was purified by silica gel chromatography(DCM/MeOH=40/1) to afford the title compound as yellow solid (45 mg, 23%yield). [Method 5]

Example 59 Method 63-methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-morpholine

A mixture of Intermediate Q30 (100 mg, 0.266 mmol), Intermediate E (61.5mg, 0.266 mmol), xantphos (30.7 mg, 0.053 mmol), Pd₂(dba)₃ (24.33 mg,0.027 mmol) and DIPEA (0.093 ml, 0.531 mmol) in DMF (5 ml) was bubbledwith Ar gas for 10 min, then the reaction tube was sealed and heated at110° C. for 1 h under MW radiation. The solvent was removed underreduced pressure. The residue was purified by silica gel chromatography(DCM/MeOH=40/1) and then was repurified by prep-HPLC to afford the titlecompound as white solid (40 mg, 32.9% yield). [Method 6]

Example 63 Reference Example6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline

A mixture of 6-bromoquinoline (72.0 mg, 0.346 mmol), Intermediate E (80mg, 0.346 mmol), Pd₂(dba)₃ (31.7 mg, 0.035 mmol), xantphos (40.0 mg,0.069 mmol) and DIPEA (0.242 ml, 1.384 mmol) in DMF (10 ml) was bubbledwith N₂ for 15 min. The reaction was stirred at 100° C. for 2 h under MWradiation. The mixture was concentrated and the residue obtained waspurified by silica gel chromatography eluted with DCM/MeOH (from 100% to90%) to afford the title compound as yellow solid (63 mg, 45.7% yield).¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.65 (d, 1H), 8.59 (s, 1H), 8.28 (m,2H), 7.98 (m, 3H), 7.89 (s, 1H), 7.81 (d, 1H), 7.59 (d, 1H), 7.50 (m,1H), 3.84 (s, 3H). LCMS (method B): [M+H]⁺=359, t_(R)=2.0 min.

Example 65 Reference Example6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinoline

A mixture of Intermediate F (40 mg, 0.160 mmol), 6-bromoquinoline (33.4mg, 0.160 mmol), xantphos (18.57 mg, 0.032 mmol), Pd₂(dba)₃ (14.69 mg,0.016 mmol) and DIPEA (0.111 ml, 0.642 mmol) in DMF (5 ml) was bubbledwith N₂ for 15 min and then was heated to 120° C. for 5 h under MWradiation. The solvent was removed under reduced pressure. The residuewas purified with by silica gel chromatography eluted with DCM/MeOH(from 100% to 90%) to afford the title compound as a brownish solid (20mg, 29.8% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 8.87 (s, 1H), 8.50 (s,1H), 8.35 (s, 1H), 8.29 (d, 1H), 8.04 (m, 1H), 7.98 (d, 1H), 7.91 (d,1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.53 (m, 1H), 3.84 (s, 3H). LCMS(method B): [M+H]⁺=377, t_(R)=1.95 min.

Example 66 Reference Example6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(1-methyl-1H-pyrazol-4-yl)quinoline

A mixture of Intermediate F (30 mg, 0.120 mmol), Intermediate Q32 (43.0mg, 0.120 mmol), Pd₂(dba)₃ (11.01 mg, 0.012 mmol), xantphos (13.93 mg,0.024 mmol) and DIPEA (0.084 ml, 0.481 mmol) in DMF (0.5 ml) was bubbledwith N₂ for 15 min. The mixture was heated at 105° C. for 5 h under MWradiation. The solvent was removed under reduced pressure. The residuewas purified by silica gel chromatography eluted with DCM/MeOH (from100% to 90%) to afford the title compound as a white solid (20 mg, 32.8%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.14 (s, 1H), 9.50 (s, 1H), 8.34(s, 3H), 8.03 (d, 2H), 7.94 (s, 1H), 7.85 (d, 1H), 7.69 (s, 1H), 7.58(d, 1H), 3.90 (s, 3H), 3.83 (s, 3H). LCMS (method B): [M+H]⁺=457,t_(R)=2.10 min.

Example 67 Method 83-(4,4-Difluoro-piperidin-1-yl)-6-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinoline

A mixture of Intermediate F (62.9 mg, 0.252 mmol), Intermediate Q8 (100mg, 0.252 mmol), Pd₂(dba)₃ (23.10 mg, 0.025 mmol), xantphos (29.2 mg,0.050 mmol) and DIPEA (0.132 ml, 0.757 mmol) in DMF (3 ml) was bubbledwith argon for 10 min. Then the mixture was heated to 100° C. undermicrowave radiation for 45 min. The solvent was removed and the residuewas purified by prep-HPLC to give white solid (35 mg, 28% yield).[Method 8]

Example 69 Method 94-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholine

A mixture of Intermediate E (1.27 g, 5.52 mmol), Intermediate Q33 (2 g,5.52 mmol), Pd₂(dba)₃ (505 mg, 0.55 mmol), xantphos (639 mg, 1.10 mmol)and DIPEA (2.41 ml, 13.8 mmol) in DMF (20 ml) was bubbled with N₂ for 15min and then was heated at 100° C. for 8 h. The solvent was removedunder reduced pressure. The residue was purified by silica gelchromatography eluted with MeOH in DCM (from 0 to 10%) to afford thetitle compound as a yellow solid (1.35 g, 55% yield). [Method 9]

Example 73 Reference Compound2-(4-(3-(3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1H-pyrazol-1-yl)ethanol

The title compound was prepared using the same procedure as described inthe synthesis of example 2. ¹H-NMR (400 MHz, DMSO-d₆) δ ppm 9.50 (d,1H), 9.20 (s, 1H), 9.10 (s, 1H), 8.91 (s, 1H), 8.37 (m, 3H), 8.12 (m,5H), 4.34 (m, 2H), 4.0 (s, 3H), 3.94 (t, 2H). LCMS (method B):[M+H]⁺=469, t_(R)=2.0 min.

Example 76 Method 10 According to Scheme 2)1-(3-((3-(4-hydroxypiperidin-1-yl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-ethanoneO-(2-hydroxyethyl)oxime

6-((6-Bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)-3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl) quinoline (76.1)

To a solution of Intermediate I (500 mg, 2.173 mmol) and IntermediateQ27 (1066 mg, 2.173 mmol) in DMF (8 ml) was added xantphos (251 mg,0.435 mmol), Pd₂(dba)₃ (199 mg, 0.217 mmol) and DIEA (1.139 ml, 6.52mmol), and the tube was bubbled with Argon gas for several minutes, andthe tube was sealed and heated to 100° C. for 5 hr. The reaction wasmonitored by TLC. The solvent was removed under reduced pressure and theresidue was purified by flash chromatography and eluented with DCM/MeOH(40:1˜20:1) to give desired product (76.1) as yellow powder (438 mg,yield 33.6%). ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.75 (s, 1H), 8.34 (s, 1H),7.92 (d, 1H), 7.77 (d, 1H), 7.54 (s, 1H), 7.36-7.42 (m, 2H), 7.18 (s,1H), 3.96-3.98 (m, 1H), 3.49-3.35 (m, 2H), 3.17-3.23 (m, 2H), 1.88-1.94(m, 2H), 1.69-1.75 (m, 2H), 0.92 (s, 9H), 0.09 (s, 6H).

3-(4-((Tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-((6-(1-ethoxyvinyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinoline(76.2)

The solution of (76.1) (100 mg, 0.175 mmol) and PdCl₂(PPh₃)₂ (12.30 mg,0.018 mmol) in 1,4-Dioxane (2 ml) was bubbled with Argon for 5 mins, Tinreagent (95 mg, 0.263 mmol) was added by injection and the mixture wasbubbled with Argon for another 5 mins, and the tube was sealed andheated to 120° C. for 3 hr. Monitored the reaction by TLC. The solventwas evaporated and the residue was purified by flash chromatography andeluented with DCM/MeOH (40:1˜20:1) to give pure desired product (76.2)as orange oil (90 mg, yield 90%). ¹H-NMR (400 MHz, CDCl₃) δ ppm 8.73 (s,1H), 8.41 (s, 1H), 7.97 (d, 1H), 7.78 (d, 1H), 7.57 (s, 2H), 7.42-7.49(m, 2H), 7.21 (s, 1H), 4.68 (s, 1H), 4.36 (s, 1H), 3.88-3.98 (m, 3H),3.48-3.53 (m, 2H), 3.18-3.23 (m, 2H), 1.88-1.91 (m, 2H), 1.66-1.74 (m,2H), 1.38 (t, 3H), 0.91 (s, 9H), 0.09 (s, 6H).

1-(3-((3-(4-Hydroxypiperidin-1-yl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone(76.3)

To the solution of (76.2) (90 mg, 0.160 mmol) in THF (2 ml) was addedabout 2 N HCl (1 mL) at rt and the mixture was continue stirred for 30mins, Checked the reaction by LCMS and TLC. The reaction solution wasneutralized with sat.NaHCO₃ aqueous until the pH to 8˜9 and extractedwith DCM for three times, the combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give crudeproduct which was purified by flash chromatography and eluented withDCM/MeOH (40:1˜20:1) to obtained pure desired product (76.3) as yellowsolid (42 mg, yield 62.5%). ¹H-NMR (400 MHz, MeOH-d₄) δ ppm 8.95 (s,1H), 8.72 (s, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.75 (s,1H), 7.39-7.43 (m, 2H), 3.78-3.84 (m, 1H), 3.68-3.74 (m, 2H), 3.02-3.08(m, 2H), 2.57 (s, 3H), 1.98-2.01 (m, 2H), 1.62-1.71 (m, 2H). LCMS(method A): [M+H]⁺=420.1, t_(R)=2.013 min.

(E)-1-(3-((3-(4-Hydroxypiperidin-1-yl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-(2-hydroxyethyl)oxime (Example 76)

To the solution of (76.3) (30 mg, 0.072 mmol) and 2-(aminooxy)ethanol(6.06 mg, 0.079 mmol) in MeOH (3 ml) was added a drop of 2 N HCl, sealedthe tube and stirred at 50° C. for overnight. The solvent was evaporatedunder reduced pressure to give crude desired product as orange oil whichwas purified by chromatography and eluent with DCM/MeOH (30:1-20:1) toobtained pure desired product as yellow solid (25 mg, 69.4%).

Example 77 Method 11 According to Scheme 2(E)-1-(3-((3-morpholinoquinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneoxime

4-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)morpholine(77.1)

A microwave tube was charged with Intermediate I (127 mg, 0.552 mmol),Intermediate Q33 (200 mg, 0.552 mmol), Pd₂(dba)₃ (50.5 mg, 0.055 mmol),Xantphos (35.1 mg, 0.061 mmol) and DIPEA (143 mg, 1.104 mmol), followedby addition of DMF (8 ml), after which the reaction was bubbled by N2for 5 min, sealed and irritated by microwave at 110° C. for 45 min. Thereaction was evaporated to dryness and the residue was purified by flashchromatography (CombiFlash, ISCO, eluent MeOH/DCM from 0 to 15%) toafford the title compound (110 mg, yield 45.1%). LCMS (method A):[M+H]⁺=441.5, t_(R)=2.34 min. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.29 (br.s., 4H) 3.92 (br. s., 4H) 7.24 (br. s., 1H) 7.43 (t, 2H) 7.59 (s, 1H)7.79 (d, 1H) 7.98 (d, 1H) 8.36 (s, 1H) 8.77 (br. s., 1H)

4-(6-((6-(1-ethoxyvinyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)morpholine(77.2)

The solution of (77.1) (110 mg, 0.249 mmol) and PdCl₂(PPh₃)₂ (17.45 mg,0.025 mmol) in 1,4-dioxane (4 ml) was bubbled by N₂ for 5 min.Tributyl(1-ethoxyvinyl)stannane (135 mg, 0.373 mmol) was added. Thereaction tube was flushed by N2 for 5 min again and sealed. Thesealed-tube was stirred at 120° C. for 2 h. The reaction was evaporatedto dryness and the residue was directly used in the next step. LCMS(method A): [M+H]⁺=433.6, t_(R)=2.54 min.

1-(3-((3-morpholinoquinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone(77.3)

The crude (77.2) was dissolved in THF (20 ml) and 1 ml of HCl (2N) wasadded. The mixture was stirred at rt for 10 min. The mixture wasneutralized by saturated aqueous NaHCO₃ and evaporated to dryness. Theresidue was purified by column chromatography (CombiFlash-ISCO, eluentDCM/MeOH from 20/1 to 8/1 for 40 min gradiently) to afford the titlecompound (40 mg, yield 39.8% over 2 steps). LCMS (method A):[M+H]⁺=405.6, t_(R)=2.08 min. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.57 (s.,3H) 3.17-3.34 (t, 4H) 3.82-4.00 (t, 4H) 7.15 (d, 1H) 7.46 (d, 1H) 7.64(s, 1H) 7.88 (s, 2H) 7.93 (d, 1H) 8.76 (d, 1H) 8.78 (s, 1H)

(E)-1-(3-((3-morpholinoquinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneoxime (Example 77)

To a solution of (77.3) (10 mg, 0.025 mmol) and hydroxylaminehydrochloride (6.86 mg, 0.099 mmol) in EtOH (5 ml) was added 0.01 ml ofHCl (2 N) and the mixture was stirred in a sealed tube at 80° C.overnight. The mixture was evaporated to dryness and dissolved in H₂Oagain, which was neutralized immediately by NaHCO₃ until pH reachedabout 9. The resulted precipitate was filtered quickly. The precipitatewas dissolved in DCM/MeOH (10/1) and washed again by water. The organicphase was dried over Na₂SO₄, filtered and evaporated to give the titlecompound (6.8 mg, yield 60.1%).

Example 78 Method 12(E)-1-(3-((3-morpholinoquinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-(2-hydroxyethyl)oxime

To a solution of1-(3-((3-morpholinoquinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone(77.3) (15 mg, 0.037 mmol) and 2-(aminooxy)ethanol (5.7 mg, 0.074 mmol)in EtOH (5 ml) was added 2 drops of HCl (2 N) and the mixture wasstirred in a sealed tube at 80° C. overnight. The mixture was evaporatedto dryness and the residue was triturated in H₂O. The resultedprecipitate was filtered quickly and dried to afford the title compoundas HCl salt (11.1 mg, yield 55.8%).

Example 79 Method 13 According to Scheme 2(E)-1-(3-(3-(morpholinomethyl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneoxime

4-((6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)methyl)-morpholine(79.1) (Method 13A)

A microwave tube was charged with Intermediate I (200 mg, 0.869 mmol),Intermediate Q35 (327 mg, 0.869 mmol), Pd₂(dba)₃ (80 mg, 0.087 mmol),Xantphos (55.3 mg, 0.096 mmol) and DIPEA (225 mg, 1.738 mmol), followedby addition of DMF (6 ml), after which the reaction was bubbled by N₂for 5 min, sealed and stirred at 80° C. for 2 h. The reaction wasevaporated to dryness and the residue was purified by flashchromatography (CombiFlash, ISCO, eluent MeOH/DCM from 0 to 15%) toafford the title compound (167 mg, yield 42.1%). LCMS (method A):[M+H]⁺=458.1, t_(R)=1.59 min.

4-((6-((6-(1-ethoxyvinyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)methyl)morpholine(79.2) (Method 13B)

The solution of (79.1) (140 mg, 0.307 mmol) and PdCl₂(PPh₃)₂ (32.3 mg,0.046 mmol) in 1,4-dioxane (6 ml) was bubbled by N₂ for 5 min.Tributyl(1-ethoxyvinyl)stannane (222 mg, 0.614 mmol) was added. Thereaction tube was flushed (not bubbled) by N₂ for 5 min again andsealed. The sealed-tube was stirred at 120° C. for 2 h. The reaction wasevaporated to dryness and the residue was purified by flashchromatography (CombiFlash, ISCO, eluent MeOH/DCM from 0 to 15%) toafford the title compound (62.8 mg, yield 45.7%). LCMS (method A):[M+H]⁺=448.1, t_(R)=3.09 min.

1-(3-((3-(morpholinomethyl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanonehydrochloride (79.3) (Method 13C)

(79.2) (62.8 mg, 0.140 mmol) was dissolved in THF (10 ml) and 0.5 ml ofHCl (2N) was added. The mixture was stirred at rt for 10 min. Aprecipitate appeared. 5 ml of MeOH was added and the solution becameclean. The mixture was stirred for another 10 min. LCMS showed thestarting material was consumed completely and about 20% di-methyl ketalside-product seems to be formed. The mixture was evaporated to dryness,which was used in next step directly. LCMS (method A): [M+H]⁺=420.0,t_(R)=2.12 min.

(E)-1-(3-(3-(morpholinomethyl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneoxime (Example 79) (Method 13D)

To a solution of (79.3) (23 mg, 0.047 mmol) and hydroxylaminehydrochloride (6.49 mg, 0.093 mmol) in EtOH (5 ml) was added 2 drops ofHCl (2 N) by a 1-ml syringe to reach pH about 5 and the mixture wasstirred in a sealed tube at 80° C. overnight. The mixture was evaporatedto dryness and dissolved in H2O again, which was neutralized immediatelyby NaHCO₃ until pH reached about 9. The resulted precipitate wasfiltered quickly. The filtrate was extracted by DCM/MeOH (10/1, 2×). Thecombined organic layers were washed by water again, dried over Na₂SO₄,filtered and evaporated to afford target the title compound (16.24 mg,yield 80%).

Example 80 Method 14(E)-1-(3-((3-(morpholinomethyl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-(2-hydroxyethyl)oxime (Example 80)

To a solution of1-(3-(3-(morpholinomethyl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanonehydrochloride (79.3) (23 mg, 0.047 mmol) and 2-(aminooxy)ethanol (10.80mg, 0.140 mmol) in MeOH (5 ml) was added 2 drops of HCl (2 N) by a 1-mlsyringe to reach pH about 3 and the mixture was stirred in a sealed tubeat 85° C. for 3 h. The mixture was evaporated to dryness and the residuewas dissolved in water. The solution was neutralized by adding solidNaHCO₃ until pH reached 9, then extracted by DCM (3×). The combinedorganic layers were washed by water again, dried over Na₂SO₄, filteredand evaporated. The residue was purified by preparative base HPLC(gradient eluent NB from 20/80 to 95/5. mobile phase A: NH₄OH/CH₃CN0.04%; mobile phase B: NH₄OH/H₂O 0.04%). The desired fractions werecollected, evaporated by BUCHI under 30 mbar at 35° C. to remove CH₃CN.The remained solution was lyophilized to afford the title compound (12.2mg, yield 54.2%).

Example 81 Method 15 According to Scheme 2(S,E)-1-(3-(3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-2-hydroxyethyl oxime hydrochloride

(S)-1-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)-N,N-dimethylpyrroli-din-3-amine(81.1)

The title compound was prepared using the same procedure as describedfor 79.1 (method 13A). LCMS (method A): [M+H]⁺=469.0, t_(R)=1.64 min.

(S)-1-(6-(6-(1-ethoxyvinyl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-N,N-dimethylpyrrolidin-3-amine(81.2)

The solution of (81.1) (256.5 mg, 0.546 mmol) and PdCl₂(PPh₃)₂ (38.4 mg,0.055 mmol) in DMF (10 ml) was bubbled by N₂ for 5 min.Tributyl(1-ethoxyvinyl)stannane (296 mg, 0.820 mmol) was added. Thereaction tube was flushed by N₂ for 5 min again and sealed. Thesealed-tube was stirred at 85° C. for 16 h. The mixture was evaporatedto dryness and the residue was purified by flash chromatography(CombiFlash, ISCO, eluent MeOH/DCM from 0 to 10%) to afford the titlecompound (35 mg, yield 13.91%). LCMS (method A): [M+H]⁺=461.2,t_(R)=1.96 min.

(S)-1-(3-(3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6yl)ethanone hydrochloride (81.3)

(81.2) (35 mg, 0.076 mmol) was dissolved in THF (5 ml) and 0.1 ml of HCl(2N) was added. The mixture was stirred at rt for 30 min. The mixturewas evaporated to dryness, which was used in next step directly. LCMS(method A): [M+H]⁺=433.2, t_(R)=1.51 min.

(S,E)-1-(3-(3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-2-hydroxyethyl oxime hydrochloride (Example 81)

To a solution of (81.3) (12 mg, 0.026 mmol) and 2-(aminooxy)ethanol(9.86 mg, 0.128 mmol) in MeOH (5 ml) was added 2 drops of HCl (2 N) by a1-ml syringe to reach pH about 3 and the mixture was stirred in a sealedtube at 85° C. for 16 h. The mixture was evaporated to dryness and theresidue was purified by preparative acid HPLC (gradient eluent NB from20/80 to 95/5. mobile phase A: TFA/CH₃CN 0.05%; mobile phase B: TFA/H₂O0.05%). The desired fractions were collected, evaporated by BUCHI under30 mbar at 35° C. to remove CH₃CN. The remained solution was lyophilizedto afford title compound (11.5 mg, yield 85%).

Example 82 Method 16(S,E)-1-(3-(3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneoxime hydrochloride

To a solution of (81.3) (12 mg, 0.026 mmol) and hydroxylaminehydrochloride (7.11 mg, 0.102 mmol) in MeOH (3 ml) was added 2 drops ofHCl (2N) by a 1-ml syringe to reach pH about 3 and the mixture wasstirred in a sealed tube at 85° C. for 3 h. The mixture was evaporatedto dryness and the residue was purified by preparative acid HPLC(gradient eluent NB from 20/80 to 95/5. mobile phase A: TFA/CH₃CN 0.05%;mobile phase B: TFA/H₂O 0.05%). The desired fractions were collected,evaporated by BUCHI under 30 mbar at 40° C. to remove CH₃CN. Theremained solution was lyophilized to afford the title compound (8.1 mg,yield 65.4%).

Example 83 Method 17 According to Scheme 2(E)-1-(3-(3-(tetrahydro-2H-pyran-4-ylamino)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-2-hydroxyethyl oxime hydrochloride

6-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-N-(tetrahydro-2H-pyran-4-yl)quinolin-3-amine(83.1)

A microwave tube was charged with Intermediate I (200 mg, 0.869 mmol),Intermediate Q9 (327 mg, 0.869 mmol), Pd₂(dba)₃ (80 mg, 0.087 mmol),Xantphos (55.3 mg, 0.096 mmol) and DIPEA (225 mg, 1.738 mmol), followedby addition of DMF (5 ml), after which the reaction was bubbled by N₂for 5 min, sealed and stirred at 80° C. for 16 h. The reaction wasevaporated to dryness and the residue was purified by flashchromatography (CombiFlash, ISCO, eluent MeOH/DCM from 0 to 15%) toafford the title compound (150 mg, yield 37.8%). LCMS (method A):[M+H]⁺=456.0, t_(R)=2.33 min.

7-((6-(1-ethoxyvinyl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)-N-(tetrahydro-2H-pyran-4-yl)quinolin-3-amine(83.2)

The title compound was prepared using the same procedure as described inthe synthesis of 79.2 (method 13B). LCMS (method A): [M+H]⁺=448.2,t_(R)=2.55 min.

1-(3-(3-(tetrahydro-2H-pyran-4-ylamino)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanonehydrochloride (83.3)

The title compound was prepared using the same procedure as described inthe synthesis of 81.3 (method 15C). LCMS (method A): [M+H]⁺=420.1,t_(R)=2.10 min.

(E)-1-(3-(3-(tetrahydro-2H-pyran-4-ylamino)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-2-hydroxyethyl oxime hydrochloride (Example 83)

The title compound was prepared using the same procedure as described inthe synthesis of Example 81 (method 15D).

Example 85 Method 18 According to Scheme 2(S,E)-1-{3-[3-(3-dimethylamino-pyrrolidin-1-yl)-quinolin-6-ylthio]-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-ethanoneO-(2-hydroxy-ethyl)-oxime hydrochloride

(S)-1-(6-(6-bromo-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-N,N-dimethylpyrrolidin-3-amine(85.1)

A microwave tube was charged with Intermediate H (600 mg, 2.419 mmol),Intermediate Q2 (314 mg, 0.806 mmol), Pd₂(dba)₃ (148 mg, 0.161 mmol),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (103 mg, 0.177mmol) and DIPEA (417 mg, 3.23 mmol), followed by addition of DMF (20ml), after which the reaction was bubbled by N2 for 5 min, sealed andirritated by microwave at 100° C. for 40 min. Then another 0.2 eq. ofPd₂(dba)₃ and another 0.22 eq. of Xantphos was added. The mixture wasirritated by microwave at 100° C. for another 40 min and then stirred at100° C. for 5 h. The mixture was evaporated to dryness and the residuewas purified by flash chromatography (CombiFlash, ISCO, eluent MeOH/DCMfrom 0 to 10%) to afford the title compound (185 mg, 66.4% pure, yield31.3%). LCMS (method A): [M+H]⁺=486.8, t_(R)=2.30 min.

(S)-1-(6-(6-(1-ethoxyvinyl)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-N,N-dimethylpyrrolidin-3-amine(85.2)

The solution of (85.1) (175 mg, 0.359 mmol) and PdCl₂(PPh₃)₂ (37.8 mg,0.054 mmol) in DMF (10 ml) was bubbled by N2 for 5 min.tributyl(1-ethoxyvinyl)stannane (195 mg, 0.539 mmol) was added. Thereaction tube was flushed by N₂ for 5 min again and sealed. Thesealed-tube was stirred at 90° C. for 2 h. Then the reaction wascontinued at 110° C. for 16 h. The mixture was evaporated to dryness andthe residue was purified by column chromatography (CombiFlash, ISCO,eluent MeOH/DCM from 0 to 10%) to afford the target product (40 mg, 30%pure, yield 6.98%). LCMS (method A): [M+H]⁺=479.1, t_(R)=1.92 min.

(S)-1-(3-(3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanonehydrochloride (85.3) and(S)-1-(2-((3-(3-(dimethylamino)pyrroli-din-1-yl)quinolin-6-yl)thio)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)ethanone(85.4)

To a solution of (85.2) (40 mg, 0.025 mmol, 30% pure) in THF (10 ml) wasadded 2 drops of HCl (2 N) and the mixture was stirred for 5 min. Themixture was evaporated to dryness and the residue was purified bypreparative HPLC (gradient eluent: NB from 20/80 to 95/5, A=CH3CN with0.05% TFA, B=H2O with 0.05% TFA) to afford the title compounds as HClsalt.

(S)-1-(3-(3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanonehydrochloride (85.3, 4 mg, yield 32.8%). LCMS (method A): [M+H]⁺=451.1,t_(R)=1.46 min. ¹H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 2.32-2.46 (m,1H) 2.61 (s, 3H) 2.67 (m, 1H) 2.97 (s, 6H) 3.49-3.63 (m, 1H) 3.67-3.84(m, 2H) 3.90-4.02 (m, 1H) 4.09-4.27 (m, 1H) 7.59 (d, 1H) 7.72-7.83 (m,2H) 7.87-7.97 (m, 2H) 8.61 (s, 1H) 8.89 (s, 1H).

(S)-1-(2-((3-(3-(dimethylamino)pyrrolidin-1-yl)quinolin-6-yl)thio)-8-fluoro-[1,2,4]triazolo-[1,5-a]pyridin-6-yl)ethanone(85.4, 4 mg, yield 32.8%). LCMS (method A): [M+H]⁺=451.1, t_(R)=1.77min. ¹H NMR (400 MHz, DEUTERIUM OXIDE) δ ppm 2.28-2.47 (m, 1H) 2.61-2.74(m, 1H) 2.84 (s, 3H) 2.98 (s, 6H) 3.47-3.62 (m, 1H) 3.67-3.81 (m, 2H)3.95 (t, 1H) 4.14-4.24 (m, 1H) 7.52 (d, 1H) 7.60 (d, 1H) 7.76 (br. s.,1H) 7.85 (s, 1H) 7.94 (d, 1H) 8.58 (br. s., 1H) 9.26 (s, 1H).

(S,E)-1-{3-[3-(3-dimethylamino-pyrrolidin-1-yl)-quinolin-6-ylthio]-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-6-yl}-ethanoneO-(2-hydroxy-ethyl)-oxime hydrochloride (Example 85)

The title compound was prepared from (85.3) using the same procedure asdescribed in the synthesis of Example 81 (method 15D).

Example 86 Method 19(E)-1-(3-(3-(4-methylpiperazin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-2-hydroxyethyl oxime

6-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-methylpiperazin-1-yl)quinoline(86.1)

A solution of Intermediate I (138 mg, 0.599 mmol), Intermediate Q14 (150mg, 0.4 mmol), Pd₂(dba)₃ (36.6 mg, 0.04 mmol), xantphos (46.2 mg, 0.08mmol) and DIPEA (0.14 ml, 0.799 mmol) in DMF (6 ml) was bubbled by N₂for 10 min, and then heated at 100° C. for 4 hours in oil bath. Thereaction mixture was quenched with water and extracted with EtOAc forthree times. The combined extract was washed with brine and dried overanhydrous Na₂SO₄. Solvent was evaporated and the residue was purified bysilica gel chromatography to afford the title compound (0.08 g, 44%yield). LCMS (method A): [M+H]⁺=455/457, t_(R)=1.7 min.

1-(3-(3-(4-methylpiperazin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanone(86.2)

A solution of (86.1) (80 mg, 0.176 mmol) and PdCl₂(PPh₃)₂ (12.3 mg,0.018 mmol) in dioxane (6 ml) was bubbled by N₂ for 10 min, thentributyl(1-ethoxyvinyl)stannane (127 mg, 0.351 mmol) was added and thesolution was heated at 110° C. under N₂ for 3 hours in oil bath. Thereaction mixture was quenched with KF solution and extracted with EtOAcfor three times. The combined extract was washed with brine and driedover anhydrous Na₂SO₄. Solvent was evaporated and the crude wasdissolved in MeOH (10 ml). Drops of 3N HCl solution were added and thesolution was then stirred at rt for 4 hours. Solvent was evaporated andthe residue was purified on flash chromatography (gradient eluent:MeOH/DCM from 0-10%) to afford the title compound as yellow solid (0.16g, >100%, contains some impurities). LCMS (method A): [M+H]⁺=419.2,t_(R)=1.45 min.

(E)-1-(3-(3-(4-methylpiperazin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-2-hydroxyethyl oxime (Example 86)

A solution of (86.2) (120 mg, 0.287 mmol) and 2-(aminooxy)ethanol (44.2mg, 0.573 mmol) in MeOH (10 ml) was added drops of HCl (3 N) to reach pHabout 5 and then stirred at rt for overnight. Solvent was evaporated andthe residue was purified by preparative base HPLC (gradient eluent NBfrom 20/80 to 95/5. mobile phase A: NH₄OH/CH₃CN 0.05%; mobile phase B:NH₄OH/H₂O 0.05%) to afford the title compound (20 mg, yield 15%).

The following table provides structural formula and names andcharacterizing data of the compounds of the invention described aboveand of further compounds synthesized according to the methods described.

LCMS (method) Starting Ex. Structure Name NMR Method Material  1

LCMS (method N): [M + H]⁺ = 543, t_(R) = 2.40 min. ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.40 (s, 1H), 8.15 (s, 1H), 7.82 (m, 2H), 7.64 (s, 1H),7.59 (s, 1H), 7.45 (d, 1H), 7.40 (s, 1H), 7.26 (s, 1H), 7.21 (d, 1H),6.70 (s, 1H), 4.90 (broad, 1H), 4.38 (broad, 1H), 3.92 (s, 3H),3.67~3.63 (m, 1H), 3.53~3.47 (m, 1H), 3.43~3.37 (m, 1H), 3.26~3.24 (m,1H), 2.35~2.27 (m, 1H), 2.02~2.00 (broad, 1H), 1.44 (s, 9H). 1AIntermediates E + Q1  2

LCMS (method N): [M + H]⁺ = 443, t_(R) = 1.65 min. ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 8.47 (s, 1H), 8.37 (s, 1H), 8.03 (s, 1H), 7.86~7.82 (m,2H), 7.78~7.71 (m, 2H), 7.57 (s, 1H), 7.21 (d, 1H), 6.95 (s, 1H), 3.89(s, 3H), 3.67 (broad, 1H), 3.59~3.54 (m, 2H), 3.42~3.36 (m, 1H),3.13~3.10 (m, 1H), 2.26~2.21 (m, 1H), 1.93~1.85 (broad, 1H). 1B Ex 1  3

LCMS (method N): [M + H]⁺ = 471, t_(R) = 1.63 min. ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 8.38 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.78~7.75 (m,2H), 7.67~7.62 (m, 2H), 7.44 (s, 1H), 7.13 (d, 1H), 6.78 (s, 1H), 3.85(s, 3H), 3.51~3.47 (m, 1H), 3.43~3.39 (m, 1H), 3.27~3.23 (m, 1H),3.13~3.08 (m, 1H), 2.86~2.82 (m, 1H), 2.29 (s, 6H), 2.25~2.20 (m, 1H),1.90~1.82 (m, 1H). 1A Intermediates E + Q2  4

LCMS (method N): [M + H]⁺ = 543, t_(R) = 2.48 min. ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 8.44 (s, 1H), 8.31 (d, 1H), 8.00 (s, 1H), 7.83~7.80 (m,2H), 7.74~7.67 (m, 2H), 7.54 (s, 1H), 7.21 (d, 1H), 6.97 (s, 1H), 4.02(broad, 1H), 3.88 (s, 3H), 3.66~3.62 (m, 1H), 3.48~3.44 (m, 2H),3.28~3.24 (m, 1H), 2.20~2.19 (m, 1H), 1.92~1.91 (m, 1H), 1.42 (d, 9H).1A Intermediates E + Q3  5

LCMS (method N): [M + H]⁺ = 443, t_(R) = 1.64 min. ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 8.43 (s, 1H), 8.30 (s, 1H), 7.99 (s, 1H), 7.82~7.79 (m,2H), 7.72~7.63 (m, 2H), 7.53 (s, 1H), 7.21~7.14 (m, 1H), 6.92 (s, 1H),3.95 (broad, 1H), 3.87 (s, 3H), 3.69~3.45 (m, 1H), 3.21~3.17 (m, 1H),3.14~3.09 (m, 1H), 3.00~2.99 (m, 1H), 2.87~2.84 (m, 1H), 2.23~2.16 (m,1H), 1.93~1.77 (m, 1H). 1B Ex 4  6

LCMS (method N): [M + H]⁺ = 471, t_(R) = 1.59 min. ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 8.76 (s, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 8.03 (s, 1H),7.89 (d, 1H), 7.83~7.81 (m, 3H), 7.74 (d, 1H), 7.58 (d, 1H), 3.90 (s,3H), 3.64 (s, 2H), 2.48 (broad, 8H), 2.23 (s, 3H). 1A Intermediates E +Q4  7

LCMS (method B): [M + H]⁺ = 531, t_(R) = 1.81 min. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.45 (s, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 8.03 (s, 1H),7.80 (d, 1H), 7.72 (s, 1H), 7.68 (d, 1H), 7.16 (d, 1H), 6.94 (s, 1H),6.15 (d, 1H), 3.84 (s, 3H), 3.72 (d, 1H), 1.84 (d, 2H), 1.22 (s, 7H),1.04 (m, 8H). 2 Intermediates F + Q31  8

LCMS (method B): [M + H]⁺ = 489, t_(R) =1.85 min. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.44 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.01 (s, 1H),7.81 (d, 1H), 7.68 (d, 1H), 7.55 (s, 1H), 7.18 (d, 1H), 6.94 (s, 1H),6.26 (d, 1H), 3.84 (s, 3H), 3.28 (m, 1H), 2.70 (m, 2H), 2.16 (s, 3H),2.01 (m, 2H), 1.89 (m, 2H), 1.41 (m, 2H). 2 Intermediates F + Q34  9

LCMS (method N): [M + H]⁺ = 458, t_(R) = 2.48 min. ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.71 (s, 1H), 8.19 (s, 1H), 7.90~7.86 (m, 2H), 7.67 (m,1H), 7.58 (m, 1H), 7.49~7.46 (m, 2H), 7.38 (d, 1H), 7.16 (s, 1H), 4.79(broad, 1H), 3.94 (s, 3H), 3.86 (broad, 1H), 3.52~3.50 (m, 1H), 3.27(broad, 1H), 3.13 (broad, 1H), 3.01-2.97 (m, 1H), 1.89~1.87 (m, 2H),1.76~1.74 (m, 1H), 1.57~1.55 (m, 2H), 1.45 (s, 9H). 1A Intermediates E +Q5 10

LCMS (method N): [M + H]⁺ = 457, t_(R)=1.68 min. ¹H-NMR (400 MHz, CDCl₃)δ ppm 8.70 (s, 1H), 8.19 (s, 1H), 7.87~7.83 (m, 2H), 7.66 (s, 1H), 7.58(s, 1H), 7.47~7.45 (m, 2H), 7.34 (dd, 1H), 7.12 (d, 1H), 3.93 (s, 3H),3.64~3.61 (m, 1H), 3.50~3.47 (m, 1H), 3.09~3.05 (m, 1H), 2.92~2.86 (m,1H), 2.76~2.71 (m, 1H), 2.10~1.96 (m, 3H), 1.91~1.86 (m, 1H), 1.73~1.69(m, 1H), 1.37~1.32 (m, 1H) 1B Ex 9 11

LCMS (method N): [M + H]⁺ = 458, t_(R) = 2.16 min. ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.41 (s, 1H), 8.29 (d, 1H), 7.98 (s, 1H), 7.81~7.78 (m,2H), 7.70 (dd, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.16 (dd, 1H), 6.90 (d,1H), 3.88~3.81 (m, 5H), 3.74~3.68 (m, 1H), 3.56~3.53 (m, 1H), 3.06 (d,2H), 2.59~2.54 (m, 1H), 2.12~2.04 (m, 1H), 1.70~1.64 (m, 1H) 1AIntermediates E + Q6 12

LCMS (method N): [M + H]⁺ = 456, t_(R) = 2.28 min. ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.48 (s, 1H), 8.23 (d, 1H), 8.04 (s, 1H), 7.87 (d, 1H),7.82~7.77 (m, 3H), 7.60 (d, 1H), 7.30 (dd, 1H), 6.98 (d, 1H), 4.84 (s,4H), 4.17 (s, 4H), 3.90 (s, 3H) 1A Intermediates E + Q7 13

LCMS (method N): [M + H]⁺ = 489, t_(R) = 1.62 min ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 8.39 (d, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.82 (s, 1H),7.74 (d, 1H), 7.60 (s, 1H), 7.59 (d, 1H), 7.25 (dd, 1H), 6.99 (d, 1H),3.88 (s, 3H), 3.64~3.53 (m, 2H), 3.41~3.35 (m, 1H), 3.23~3.19 (m, 1H),2.97~2.93 (m, 1H), 2.33 (s, 6H), 2.33~2.27 (m, 1H), 1.95~1.90 (m, 1H) 1AIntermediates F + Q2 14

LCMS (method N): [M + H]⁺ = 529, t_(R) = 1.67 min. ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 8.70 (s, 1H), 8.36 (s, 1H), 8.05 (s, 1H), 7.84 (s, 1H),7.80 (d, 1H), 7.68 (s, 1H), 7.62 (d, 1H), 7.41~7.38 (m, 2H), 3.89~3.85(m, 5H), 2.82 (t, 2H), 2.66 (s, 4H), 2.27 (broad, 1H), 2.08~2.05 (m,2H), 1.81 (s, 4H), 1.67~1.62 (m, 2H) 1A Intermediates F + Q18 15

LCMS (method B): [M + H]⁺ = 471, t_(R) = 1.68 min. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.53 (s, 1H), 8.39 (d, 1H), 8.30 (s, 1H), 7.98 (s, 1H),7.96 (d, 1H), 7.78 (dd, 1H), 7.67 (d, 1H), 7.52 (d, 1H), 7.14 (d, 1H),6.94 (d, 1H), 6.25 (d, 1H), 3.85 (s, 3H), 3.22 (m, 1H), 2.70 (m, 2H),2.16 (s, 3H), 2.01 (m, 2H), 1.88 (m, 2H), 1.44 (m, 2H). 2 IntermediatesE + Q34 17

LCMS (method N): [M + H]⁺ = 471, t_(R) = 2.29 min ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 2.00-2.06 (m, 2H) 2.35 (s, 3H) 2.53-2.63 (m, 2H) 2.75 (m,2H) 3.51-3.59 (m, 2H) 3.61-3.70 (m, 2H) 3.90 (s, 3H) 7.15 (s, 1H) 7.25(d, 1H) 7.58 (s, 1H) 7.69- 7.81 (m, 2H) 7.81-7.90 (m, 2H) 8.05 (s, 1H)8.49 (d, 1H) 8.54 (d, 1H). 1A Intermediates E + Q10 18

LCMS (method O): [M + H]⁺ = 557, t_(R) = 3.69 min ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 0.94 (s, 5H) 1.15 (s, 4H) 1.83-1.98 (m, 2H) 3.36 (m, 2H)3.58-3.72 (m, 4H) 3.72-3.82 (m, 2H) 3.91 (s, 3H) 7.22 (s, 1H) 7.25-7.36(m, 1H) 7.58 (s, 1H) 7.70- 7.83 (m, 2H) 7.83-7.92 (m, 2H) 8.07 (s, 1H)8.49 (d, 1H) 8.57 (s, 1H). 1A Intermediates E + Q11 19

LCMS (method N): [M + H]⁺ = 457, t_(R) = 1.64 min ¹H-NMR (400 MHz,CDCl₃) δ ppm 1.85-1.99 (m, 2H) 2.80 (t, 2H) 3.05 (t, 2H) 3.60 (t, 2H)3.65 (t, 2H) 3.93 (s, 3H) 6.84- 6.92 (m, 1H) 7.24 (d, 1H) 7.41 (s, 1H)7.46 (d, 1H) 7.60 (s, 1H) 7.67 (s, 1H) 7.79 (d, 1H) 7.85 (d, 1H) 8.19(s, 1H) 8.58 (d, 1H). 1B Ex 18 20

LCMS (method N): [M + H]⁺ = 557, t_(R) = 2.47 min ¹H-NMR (400 MHz,CDCl₃) δ ppm 1.47 (s, 9H) 1.57-1.61 (m, 2H) 2.10 (d, 2H) 2.96 (t, 2H)3.72 (d, 2H) 3.96 (s, 3H) 4.51 (m, 1) 7.17 (s, 1H) 7.39 (d, 1H) 7.49 (d,1H) 7.60 (s, 1H) 7.66 (s, 1H) 7.89 (t, 1H) 8.20 (s, 1H) 1A IntermediatesE + Q12 21

LCMS (method N): [M + H]⁺ = 457, t_(R) = 1.54 min ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 1.73-1.81 (m, 2H) 2.12 (d, 2H) 2.88 (t, 2H) 3.32-3.35 (m,1H) 3.85 (d, 2H) 3.88 (s, 3H) 7.27-7.41 (m, 2H) 7.58 (s, 1H) 7.68-7.75(m, 2H) 7.78-7.82 (m, 2H) 8.01 (s, 1H) 8.41 (s, 1H) 8.63 (s, 1H) 1B Ex20 22

LCMS (method O): [M + H]⁺ = 557, t_(R) = 2.52 min ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.33-1.45 (m, 2H) 1.48 (s, 9 H) 2.06 (d, 2H) 2.98 (t, 2H)3.47 (m, 1H) 3.95 (s, 3H) 4.00-4.17 (m, 2H) 6.83 (s, 1H) 7.31 (d, 1H)7.45 (s, 1H) 7.47 (d, 1H) 7.59 (s, 1H) 7.67 (s, 1H) 7.86 (t, 2H) 8.20(s, 1H) 8.37 (s, 1H) 1A Intermediates E + Q13 23

LCMS (method O): [M + H]⁺ = 457, t_(R) = 2.33 min ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.65-1.84 (m, 2H) 2.23 (d, 2H) 3.18 (t, 2H) 3.48 (d, 2H)3.62 (m, 1H) 3.85 (s, 3H) 7.04 (s, 1H) 7.14 (d, 1H) 7.42 (s, 1H) 7.63(m, 2H) 7.75 (m., 2H) 7.97 (s, 1H) 8.32 (s, 1H) 8.36 (br. s., 1H) 1B Ex22 24

LCMS (method B): [M + H]⁺ = 475, t_(R) = 1.63 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.81 (s, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 8.03 (s, 1H),7.83 (d, 1H), 7.79 (d, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 7.35 (d, 1H),3.83 (s, 3H), 3.25 (t, 4H), 2.49 (t, 4H), 2.21 (s, 3H) 2 IntermediatesF + Q14 25

LCMS (method B): [M + H]⁺ = 476, t_(R) = 2.21 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.46 (s, 1H), 3.39 (d, 1H), 8.34 (s, 1H), 8.03 (s, 1H),7.83 (d, 1H), 7.69 (d, 1H), 7.50 (s, 1H), 7.19 (d, 1H), 6.99 (s, 1H),6.36 (d, 1H), 3.84 (m, 2H), 3.83 (s, 3H), 3.46 (m, 1H), 3.42 (m, 2H),1.88 (m, 2H), 1.37 (m, 2H) 2 Intermediates F + Q9 26

LCMS (method N): [M + H]⁺ = 543, t_(R) = 2.51 min. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.50 (s, 9 H) 3.26 (br, 4H) 3.64 (br, 4H) 3.96 (s, 3H) 7.25(s, 1H) 7.41-7.57 (m, 3H) 7.61 (s, 1H) 7.69 (s, 1H) 7.90 (d, 1H)8.02-8.08 (m., 1H) 8.21 (s, 1H) 8.72 (s, 1H) 1A Intermediates E + Q15 27

LCMS (method N): [M + H]⁺ = 443, t_(R) = 1.62 min ¹H NMR (400 MHz,MeOH-d₄) δ ppm 2.97-3.02 (m., 4H) 3.20-3.25 (m 4H) 3.87 (s, 3H)7.22-7.34 (m, 2H) 7.56 (s, 1H) 7.67-7.71 (m, 2H) 7.73-7.85 (m, 2H) 7.99(s, 1H) 8.41 (s, 1H) 8.61 (s., 1H) 1B Ex 26 28

LCMS (method N): [M + H]⁺ = 525, t_(R) = 2.42 min. ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.72 (d, 1H), 8.20 (s, 1H), 7.89~7.86 (m, 2H), 7.68 (s,1H), 7.59 (s, 1H), 7.51~7.46 (m, 1H), 7.39 (dd, 1H), 7.12 (d, 1H), 3.95(s, 3H), 3.30 (t, 4H), 3.06 (q, 2H), 2.88 (t, 4H) 1C Ex 27 29

LCMS (method N): [M + H]⁺ = 501, t_(R) = 1.35 min ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.88-2.03 (m, 2H) 2.62-2.67 (m, 4H) 2.83-3.03 (m, 2H)3.47-3.70 (m, 6H) 7.12 (d, 1H) 7.23 (d, 1H) 7.58 (s, 1H) 7.67-7.78 (m,2H) 7.78-7.88 (m, 2H) 8.02 (s, 1H) 8.46 (s, 1H) 8.52 (s, 1H) 1D Ex 19 30

LCMS (method O): [M + H]⁺ = 525, t_(R) = 1.00 min ¹H NMR (400 MHz,CDCl₃) δ ppm 0.83-0.90 (m, 1H) 1.24- 1.28 (m, 2H) 1.46-1.50 (m, 2H)1.57-1.86 (m, 7H) 1.91- 2.11 (m, 2H) 2.58-2.65 (m, 5H) 2.78-2.82 (m, 2H)3.74- 3.88 (m, 2H) 3.93 (s, 3H) 7.10 (s, 1H) 7.30-7.41 (m, 1H) 7.45-7.47(m., 2H) 7.59 (s, 1H) 7.66 (s, 1H) 7.83-7.87 (m, 2H) 8.19 (s, 1H) 8.71(s, 1H) 1A Intermediates E + Q16 31

LCMS (method O): [M + H]⁺ = 543, t_(R) = 1.72 min ¹H NMR (400 MHz,CDCl₃) δ ppm 1.36- 1.47 (m, 2H) 1.55- 1.59 (m, 4H) 1.61-1.76 (m, 2H)1.93 (d, 2H) 2.38-2.44 (m, 1H) 2.49-2.53 (m, 4H) 2.78 (t, 2H) 3.80 (d,2H) 3.91 (s, 3H) 7.08 (s, 1H) 7.12 (d, 1H) 7.31 (d, 1H) 7.47 (s, 1H)7.60-7.64 (m, 2H) 7.81 (d, 1H) 8.01 (s, 1H) 8.69 (s, 1H),. 1AIntermediates F + Q16 32

LCMS (method N): [M + H]⁺ = 525, t_(R) = 1.75 min ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.12-1.38 (m, 5H) 1.67 (d, 1H) 1.82 (d, 2H) 1.95 (d, 2H)2.31-2.35 (m, 1H) 2.74-2.84 (m, 4H) 3.34-3.38 (m, 4H) 3.91 (s, 3H) 7.32-7.44 (m, 2H) 7.69 (d, 1H) 7.74- 7.91 (m, 4H) 8.02 (s, 1H) 8.48 (s, 1H)8.71 (d, 1H) 1A Intermediates E + Q17 33

LCMS (method N): [M + H]⁺ = 511, t_(R) = 1.67 min ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.55-1.70 (m, 2H) 1.82-1.86 (m, 4H) 2.06 (d, 2H) 2.33 (t,1H) 2.70-2.74 (m, 4H) 2.80 (t, 2H) 3.84 (d, 2H) 3.88 (s, 3H) 7.35-7.37(m, 2H) 7.64 (s, 1H) 7.76- 7.78 (m, 2H) 7.81-7.89 (m, 2H) 8.04 (s, 1H)8.49 (s, 1H) 8.68 (s, 1H) 1A Intermediates E + Q9 34

LCMS (method N): [M + H]⁺ = 519, t_(R) = 2.39 min ¹H NMR (400 MHz,CDCl₃) δ ppm 3.35-3.46 (m, 8 H) 3.94 (s, 3H) 6.89-7.01 (m, 3H) 7.18 (d,1H) 7.26-7.33 (m, 2H) 7.39 (dd, 1H) 7.45-7.54 (m, 2H) 7.60 (s, 1H) 7.68(s, 1H) 7.88 (t, 2H) 8.21 (s, 1H) 8.78 (d, 1H) 1A Intermediates E + Q1935

LCMS (method N): [M + H]⁺ = 458, t_(R) = 2.28 min ¹H NMR (400 MHz,CDCl₃) δ ppm 1.22 (d, 3H) 2.51 (t, 1H) 2.85 (td, 1H) 3.46 (t, 2H) 3.67-3.81 (m, 2H) 3.89 (s, 3H) 3.98 (dd, 1H) 7.04 (d, 1H) 7.25-7.33 (m, 1H)7.38-7.47 (m, 2H) 7.61 (s, 1H) 7.62 (s, 1H) 7.78 (d, 1H) 7.80 (d, 1H)8.16 (s, 1H) 8.65 (d, 1H) 1A Intermediates E + Q20 35A

obtained by chiral separation of Ex 35 35B

obtained by chiral separation of Ex 35 36

LCMS (method N): [M + H]⁺ = 476, t_(R) = 2.31 min ¹H NMR (400 MHz,CDCl₃) δ ppm 1.23 (d, 3H) 2.53 (t, 1H) 2.87 (td, 1H) 3.48 (t, 2H) 3.68-3.84 (m, 2H) 3.91 (s, 3H) 4.00 (dd, 1H) 7.07 (d, 1H) 7.12 (d, 1H) 7.30(dd, 1H) 7.48 (d, 1H) 7.61 (s, 1H) 7.64 (s, 1H) 7.80 (d, 1H) 8.01 (s,1H) 8.66 (d, 1H) 1A Intermediates F + Q20 37

LCMS (method N): [M + H]⁺ = 472, t_(R) = 2.39 min. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.26-1.30 (m, 6H) 2.50 (t, 2H) 3.53 (d, 2H) 3.77-3.90 (m,2H) 3.95 (s, 3H) 7.10 (d, 1H) 7.38 (dd, 1H) 7.44-7.51 (m, 2H) 7.61 (s,1H) 7.68 (s, 1H) 7.86 (d, 1H) 7.89 (d, 1H) 8.20 (s, 1H) 8.71 (d, 1H) 1AIntermediates E + Q21 38

LCMS (method N): [M + H]⁺ = 490, t_(R) = 2.42 min ¹H NMR (400 MHz,CDCl₃) δ ppm 1.28-1.32 (m, 6H) 2.52 (t, 2H) 3.55 (d, 2H) 3.85 (br, 2H)3.95 (s, 3H) 7.04-7.22 (m, 2H) 7.40 (d, 1H) 7.50 (s, 1H) 7.60 (s, 1H)7.66 (s, 1H) 7.90 (d, 1H) 8.04 (S, 1H) 8.73 (s, 1H) 1A Intermediates F +Q21 39

LCMS (method N): [M + H]⁺ = 589, t_(R) = 2.63 min. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.37 (d, 6H) 1.50 (s, 9 H) 3.06 (d, 2H) 3.51 (d, 2H) 3.96(s, 3H) 4.31-4.35 (m, 2H) 7.19 (d, 1H) 7.25-7.29 (m, 3H), 7.56 (d, 1H)7.61 (s, 1H) 7.68 (s, 1H) 8.05 (s, 1H) 8.70 (d, 1H) 1A Intermediates F +Q22 40

LCMS (method N): [M + H]⁺ = 489, t_(R) = 1.71 min ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.12 (d, 6H) 2.28 (t, 2H) 2.87-2.99 (m, 2H) 3.60 (d, 2H)3.86 (s, 3H) 7.17- 7.31 (m, 2H) 7.46 (d, 1H) 7.55 (s, 1H) 7.66 (d, 1H)7.79 (s, 1H) 7.99 (s, 1H) 8.26 (s, 1H) 8.55-8.62 (m, 1H) 1B Ex 39 41

LCMS (method N): [M + H]⁺ = 571 ,t_(R) = 2.64 min ¹H NMR (400 MHz,CDCl₃) δ ppm 1.37 (d, 6H) 1.51 (s, 9 H) 3.02 (d, 2H) 3.49 (d, 2H) 3.96(s, 3H) 4.30-4.34 (m, 2H) 7.21 (s, 1H) 7.40-7.56 (m, 3H) 7.60 (s, 1H)7.69 (s, 1H) 7.89 (d, 1H) 7.98 (d, 1H) 8.21 (s, 1H) 8.70 (s, 1H) 1AIntermediates E + Q22 42

LCMS (method N): [M + H]⁺ = 471, t_(R) = 1.69 min ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.12 (d, 6H) 2.27 (t, 2H) 2.90-2.94 (m, 2H) 3.54- 3.65(m, 2H) 3.85 (s, 3H) 7.18- 7.29 (m, 2H) 7.54 (d, 1H) 7.60-7.71 (m, 2H)7.71-7.83 (m, 2H) 7.96 (s, 1H) 8.38 (s, 1H) 8.60 (d, 1H) 1B Ex 41 43

LCMS (method B): [M + H]⁺ = 472, t_(R) = 5.49 min ¹H NMR (400 MHz,CDCl₃) δ ppm 1.56-1.76 (m, 2H) 1.91- 1.95 (m., 2H) 2.99 (t, 2H) 3.23-3.55 (m, 5H) 3.86 (s, 3H) 7.03 (s, 1H) 7.24 (d, 1H) 7.33- 7.47 (m, 2H)7.60 (br, 2H) 7.74 (s, 1H) 7.76 (s, 1H) 8.13 (s, 1H) 8.63 (s, 1H) 1AIntermediates E + Q23 44

LCMS (method N): [M + H]⁺ = 490, t_(R) = 2.31 min ¹H NMR (400 MHz,CDCl₃) δ ppm 1.67-1.82 (m, 2H) 1.96- 2.09 (m, 2H) 2.99-3.15 (m, 2H) 3.38(s, 3H) 3.41-3.47 (m, 1H) 3.50-3.62 (m, 2H) 3.94 (s, 3H) 7.06-7.21 (m,2H) 7.35 (d, 1H) 7.50 (s, 1H) 7.60 (s, 1H) 7.64 (s, 1H) 7.85 (d, 1H)8.03 (s, 1H) 8.78 (d, 1H) 1A Intermediates F + Q23 45

LCMS (method N): [M + H]⁺ = 575, t_(R) = 2.54 min ¹H NMR (400 MHz,CDCl₃) δ ppm 1.07 (d, 3H) 1.50 (s, 9 H) 3.19 (d, 2H) 3.28 (br, 2H) 3.95(s, 3H) 4.01-4.10 (m, 1H) 7.10-7.20 (m, 2H) 7.41 (dd, 1H) 7.55 (d, 1H)7.59 (s, 1H) 7.66 (s, 1H) 7.93 (d, 1H) 8.02- 8.09 (m, 1H), 8.72 (d, 1H)1A Intermediates F + Q24 46

LCMS (method N): [M + H]⁺ = 475, t_(R) = 2.79 min ¹H NMR (400 MHz,CDCl₃) δ ppm 1.12 (d, 3H) 2.86-3.03 (m, 2H) 3.07-3.29 (m, 4H) 3.94 (s,3H) 4.01 (dt, 1H) 7.09 (d, 1H) 7.12-7.18 (m, 1H) 7.36 (dd, 1H) 7.53 (d,1H) 7.59 (s, 1H) 7.65 (s, 1H) 7.87 (d, 1H) 8.04 (s, 1H) 8.72 (d, 1H) 1BEx 45 47

LCMS (method A): [M + H]⁺ = 498, t_(R) = 2.33 min ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.47 (s, 1H), 8.20 (s, 1H), 7.87 (d, 2H), 7.66 (s, 1H),7.59 (s, 1H), 7.47 (m, 2H), 7.26 (m, 1H), 6.78 (m, 1H), 3.95 (s, 3H),3.76 (m, 2H), 3.70 (m, 2H), 3.49 (m, 2H), 3.30 (m, 2H), 2.00 (m, 2H),1.67 (m, 4H) 1A Intermediates E + Q25 48

LCMS (method A): [M + H]⁺ = 516, t_(R) = 2.37 min ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.47 (d, 1H), 8.03 (s, 1H), 7.89 (d, 1H), 7.64 (s, 1H),7.60 (s, 1H), 7.50 (m, 1H), 7.29 (m, 1H), 7.14 (m, 1H), 6.80 (m, 1H),3.95 (s, 3H), 3.76 (m, 2H), 3.70 (m, 2H), 3.50 (m, 2H), 3.30 (m, 2H),2.00 (m, 2H), 1.67 (m, 4H) 1A Intermediates F + Q25 49

LCMS (method A): [M+H]⁺ = 458, t_(R) = 2.07 min ¹H-NMR (400 MHz, CDCl₃)δ ppm 9.75 (d, 1H), 8.20 (s, 1H), 7.89 (m, 2H), 7.66 (s, 1H), 7.60 (s,1H), 7.53 (d, 1H), 7.49 (dd, 1H), 7.40 (dd, 2H), 5.31 (s, 1H), 3.95 (s,3H), 3.94 (m, 1H), 3.65 (m, 2H), 3.07 (m, 2H), 2.07 (m, 2H), 1.73 (m,2H) 1A & 1E Intermediates E + Q27 50

LCMS (method A): [M + H]⁺ = 476, t_(R) = 2.10 min ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 9.04 (s, 1H), 8.49 (s, 1H), 8.23 (s, 1H), 8.18 (s, 1H),8.0 (d, 1H), 7.95 (s, 1H), 7.78 (d, 1H), 7.71 (d, 2H), 3.93 (s, 3H),3.89 (m, 3H), 3.28 (m, 2H), 2.0 (m, 2H), 1.66 (m, 2H) 1A & 1EIntermediates F + Q27 51

LCMS (method A): [M + H]⁺ = 444, t_(R) = 2.11 min ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.35 (s, 1H), 8.21 (s, 1H), 7.88 (m, 2H), 7.68 (s, 1H),7.59 (s, 1H), 7.49 (m, 2H), 7.32 (d, 1H), 6.81 (s, 1H), 4.24 (m, 1H),4.16 (m, 1H), 3.95 (s, 3H), 3.85 (m, 1H), 3.73 (m, 1H), 2.35 (m, 1H),1.90 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H) 1A Intermediates E + Q26 52

LCMS (method A): [M + H]⁺ = 462, t_(R) = 2.16 min ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.61 (s, 1H), 8.05 (s, 1H), 8.00 (d, 1H), 7.67 (s, 1H),7.60 (s, 1H), 7.52 (s, 1H), 7.38 (d, 1H), 7.18 (d, 1H), 6.93 (s, 1H),4.15 (m, 1H), 4.06 (m, 1H), 3.95 (s, 3H), 3.93 (m, 1H), 3.78 (m, 1H),2.35 (m, 1H), 1.95 (m, 1H), 1.55 (m, 1H), 1.45 (m, 1H). 1A IntermediatesF + Q26 53

LCMS (method B): [M + H]⁺ = 418, t_(R) = 1.95 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.54 (s, 1H), 8.44 (s, 1H), 8.30 (s, 1H), 7.97 (d, 2H),7.77 (d, 1H), 7.68 (t, 1H), 7.51 (s, 1H), 7.13 (d, 1H), 6.92 (s, 1H),6.35 (s, 1H), 4.71 (t, 1H), 3.84 (s, 3H), 3.57 (d, 2H), 3.13 (d, 2H) 3Intermediates E + Q28 54

LCMS (method B): [M + H]⁺ = 432, t_(R) = 3.03 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.45 (t, 2H), 8.34 (d, 1H), 8.02 (d, 1H), 7.81 (dd, 1H),7.70 (dd, 1H), 7.52 (s, 1H), 7.18 (dd, 1H), 6.92 (s, 1H), 6.37 (s, 1H),4.73 (d, 1H), 3.85 (s, 3H), 3.58 (t, 2H), 3.13 (d, 2H) 3 IntermediatesF + Q28 55

LCMS (method B): [M + H]+= 392, t_(R) = 1.89 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.63 (s, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 8.0 (d, 2H),7.85 (d, 1H), 7.75 (d, 2H), 7.46 (d, 1H), 3.8 (s, 3H) 4 IntermediatesF + Q29 56

LCMS (method B): [M + H]⁺ = 374, t_(R) = 1.85 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 9.80 (d, 2H), 8.64 (d, 2H), 8.37 (d, 1H), 8.05 (t, 3H),7.90 (d, 1H), 7.84 (d, 1H), 7.79 (d, 1H), 7.74 (t, 1H), 3.8 (s, 3H). 4Intermediates E + Q29 57

LCMS (method B): [M + H]⁺ = 430, t_(R) = 2.10 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 13.08 (s, 1H), 8.81 (s, 1H), 8.59 (s, 1H), 8.37 (s, 1H),8.05 (s, 1H), 7.98 (d, 1H), 7.84 (dd, 2H), 7.59 (s, 1H), 7.42 (s, 1H),7.34 (d, 1H), 3.75 (t, 4H), 3.23 (t, 4H) 5 Intermediates C + Q33 58

LCMS (method B): [M + H]⁺ = 448, t_(R) = 2.14 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 13.11 (s, 1H), 8.81 (s, 1H), 8.50 (s, 1H), 8.40 (s, 1H),8.0 (s, 1H), 7.89 (d, 2H), 7.60 (s, 1H), 7.40 (m, 2H), 3.75 (t, 4H),3.23 (t, 4H) 5 Intermediates D + Q33 59

LCMS (method B): [M + H]⁺ = 458, t_(R) = 2.22 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.78 (d, 1H), 8.50 (s, 1H), 8.32 (s, 1H), 7.99 (t, 2H),7.80 (dd, 2H), 7.55 (d, 1H), 7.35 (d, 1H), 7.29 (t, 1H), 4.12 (m, 1H),3.93 (d, 1H), 3.83 (s, 3H), 3.71 (dd, 2H), 3.56 (dd, 1H), 3.27 (s, 1H),3.05 (m, 1H), 1.01 (s, 3H) 6 Intermediates E + Q30 60

LCMS (method B): [M + H]⁺ = 476, t_(R) = 2.26 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.78 (d, 1H), 8.47 (s, 1H), 8.34 (s, 1H), 8.03 (s, 1H),7.80 (dd, 2H), 7.56 (d, 1H), 7.35 (dd, 2H), 4.11 (m, 1H), 3.91 (d, 1H),3.90 (s, 3H), 3.71 (dd, 2H), 3.57 (t, 1H), 3.27 (d, 1H), 3.05 (t, 1H),1.01 (s, 3H) 6 Intermediates F + Q30 61

LCMS (method B): [M + H]⁺ = 478, t_(R) = 2.45 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.84 (d, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.99 (d, 1H),7.98 (s, 1H), 7.80 (m, 2H), 7.55 (d, 1H), 7.52 (d, 1H), 7.34 (dd, 1H),3.84 (s, 3H), 3.45 (t, 4H), 2.08 (m, 4H) 2 Intermediates E + Q8 62

LCMS (method B): [M + H]⁺ = 513, t_(R) = 1.80 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.55 (d, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.97 (d, 2H),7.78 (d, 1H), 7.68 (d, 2H), 7.11 (d, 1H), 6.93 (d, 1H), 6.15 (d, 1H),3.84 (s, 3H), 3.72 (d, 1H), 1.84 (d, 2H), 1.22 (m, 7H), 1.04 (m, 8H) 2Intermediates F + Q31 64

LCMS (method B): [M + H]⁺ = 448, t_(R) = 2.07 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.45 (t, 2H), 8.33 (s, 1H), 8.01 (s, 1H), 7.82 (d, 1H),7.74 (d, 1H), 7.53 (d, 1H), 7.24 (dd, 1H), 7.13 (d, 1H), 6.79 (d, 1H),4.89 (t, 2H), 4.57 (m, 1H), 4.42 (t, 2H), 3.84 (s, 3H) 2 IntermediatesF + Q36 67

LCMS (method B): [M + H]⁺ = 496, t_(R) = 2.48 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.84 (d, 1H), 8.46 (d, 1H), 8.33 (s, 1H), 8.80 (s, 1H),7.82 (d, 1H), 7.80 (s, 1H), 7.56 (d, 1H), 7.51 (d, 1H), 7.38 (dd, 1H),3.84 (s, 3H), 3.45 (t, 4H), 2.08 (m, 4H) 8 Intermediates F + Q8 68

LCMS (method B): [M + H]⁺ = 458, t_(R) = 2.20 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.54 (s, 1H), 8.39 (s, 1H), 8.31 (s, 1H), 7.98 (s, 1H),7.97 (d, 1H), 7.80 (s, 1H), 7.78 (d, 1H), 7.48 (s, 1H), 7.15 (d, 1H),6.99 (s, 1H), 6.34 (d, 1H), 3.87 (m, 2H), 3.84 (s, 3H), 3.49 (m, 1H),3.48 (m, 2H), 1.90 (m, 2H), 1.37 (m, 2H) 2 Intermediates E + Q9 69

LCMS (method B): [M + H]⁺ = 444, t_(R) = 2.09 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.81 (s, 1H), 8.55 (s, 1H), 8.30 (s, 1H), 7.99 (d, 2H),7.80 (dd, 2H), 7.57 (s, 1H), 7.41 (d, 1H), 7.32 (dd, 1H), 3.83 (s, 3H),3.75 (t, 4H), 3.22 (t, 4H) 9 Intermediates E + Q33 70

LCMS (method B): [M + H]⁺ = 462, t_(R) = 2.11 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.82 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 8.02 (s, 1H),7.83 (d, 2H), 7.58 (s, 1H), 7.42 (s, 1H), 7.39 (d, 1H), 3.84 (s, 3H),3.75 (t, 4H), 3.38 (t, 4H) 9 Intermediates F + Q33 71

LCMS (method B): [M + H]⁺ = 430, t_(R) = 2.04 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.54 (s, 1H), 8.42 (d, 1H), 8.30 (s, 1H), 7.98 (t, 2H),7.77 (dd, 1H), 7.73 (dd, 1H), 7.50 (s, 1H), 7.20 (dd, 1H), 7.10 (d, 1H),6.79 (d, 1H), 4.87 (t, 2H), 4.58 (m, 1H), 4.42 (t, 2H), 3.84 (s, 3H). 2Intermediates E + Q36 72

LCMS (method B): [M + H]⁺ = 374, t_(R) = 1.99 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 9.02 (s, 1H), 8.70 (s, 1H), 8.27 (d, 2H), 8.0 (m, 5H),7.76 (d, 1H), 4.26 (s, 2H), 3.89 (s, 6H), 3.44 (s, 4H) 2 IntermediatesG + Q33 74

LCMS (method B): [M + H]⁺ = 457, t_(R) = 1.63 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.80 (s, 1H), 8.55 (s, 1H), 8.31 (s, 1H), 7.99 (d, 1H),7.98 (s, 1H), 7.80 (dd, 2H), 7.55 (s, 1H), 7.39 (s, 1H), 7.30 (d, 1H),3.84 (s, 3H), 3.25 (t, 4H), 2.45 (t, 4H), 2.21 (s, 3H). 2 IntermediatesE + Q14 75

LCMS (method B): [M + H]⁺ = 458, t_(R) = 1.31 min ¹H-NMR (400 MHz,DMSO-d₆) δ ppm 8.82 (s, 1H), 8.59 (d, 1H), 8.32 (s, 1H), 8.17 (s, 1H),7.96 (m, 3H), 7.83 (m, 2H), 7.58 (d, 1H), 3.83 (s, 3H), 3.74 (s, 2H),3.73 (s, 6H), 3.12 (s, 2H). 2 Intermediates E + Q35 76

LCMS (method A): [M + H]⁺ = 479.1, t_(R) = 2.122 min. ¹H-NMR (400 MHz,MeOH-d₄) δ ppm 8.69 (s, 1H), 8.38 (s, 1H), 7.98 (d, 1H), 7.75- 7.78 (m,2H), 7.67 (s, 1H), 7.38 (s, 1H), 7.32 (d, 1H), 4.22-4.24 (m, 2H),3.78-3.82 (m, 3H), 3.65-3.77 (m, 2H), 2.98-3.05 (m, 2H), 2.15 (s, 3H),1.95-2.00 (m, 2H), 1.63-1.69 (m, 2H). 10 (4 steps) Intermediates I + Q2777

LCMS (method A): [M + H]⁺ = 421.1, t_(R) = 2.18 min. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.11 (s, 3H) 3.25 (br. s., 4H) 3.66-3.87 (m, 4H) 7.34 (d,1H) 7.43 (br. s., 1H) 7.61 (s, 1H) 7.82 (d, 1H) 7.84- 8.01 (m, 2H) 8.39(s, 1H) 8.83 (s, 1H) 11.60 (s, 1H) 11 (4 steps) Intermediates I + Q33 78

LCMS (method A): [M + H]⁺ = 465.2, t_(R) = 2.21 min. ¹H NMR (400 MHz,MeOH-d₄) δ ppm 2.24 (s, 3H) 3.43 (br. s., 4H) 3.82 (br. s., 2H) 3.88(br. s., 4H) 4.28 (br. s., 2H) 7.69 (d, 1H) 7.86 (br. s., 1H) 7.90 (d,1H) 7.99 (d, 1H) 8.04- 8.20 (m, 2H) 8.52 (s, 1H) 9.02 (br. s., 1H) 12Intermediate 77.3 79

LCMS (method A): [M + H]⁺ = 435.1, t_(R) = 1.54 min. ¹H NMR (400 MHz,MeOH-d₄) δ ppm 2.14 (s, 3H) 2.48 (br. s., 4H) 3.69 (m, 6H) 7.65 (d, 1H)7.81 (d, 1H) 7.89 (s, 1H) 7.97 (d, 1H) 8.04 (d, 1H) 8.16 (s, 1H) 8.43(s, 1H) 8.84 (s, 1H) 13 (4 steps) Intermediates I + Q35 80

LCMS (method A): [M + H]⁺ = 479.1, t_(R)= 1.60 min. ¹H NMR (400 MHz,CDCl₃) δ ppm 2.20 (s, 3H) 2.34-2.61 (br. s., 4H) 3.56-3.80 (m, 6H)3.86-3.98 (m, 2H) 4.26-4.39 (m, 2H) 7.62 (dd, 1H) 7.73 (s, 1H) 7.76-7.88(m, 2H) 7.94 (br. s., 1H) 8.03 (d, 1H) 8.29 (s, 1H) 8.88 (s, 1H) 14Intermediate 79.3 81

LCMS (method A): [M + H]⁺ = 492.2, t_(R) = 1.64 min. ¹H NMR (400 MHz,MeOH-d₄) δ ppm 2.20 (s, 3H) 2.30- 2.44 (m, 1H) 2.57-2.72 (m, 1H) 3.01(s, 6H) 3.46-3.60 (m, 1H) 3.67-3.84 (m, 4H) 3.90 (dd, 1H) 4.13 (quin,1H) 4.21-4.30 (m, 2H) 7.41 (d, 1H) 7.43-7.54 (m, 1H) 7.69 (d, 1H) 7.89(d, 1H) 7.86 (d, 1H) 8.03-8.11 (m, 1H) 8.46 (s, 1H) 8.60 (d, 1H) 15 (4steps) Intermediates I + Q2 82

LCMS (method A): [M + H]⁺ = 448.0, t_(R) = 2.24 min. ¹H NMR (400 MHz,MeOH-d₄) δ ppm 2.16 (s, 3H) 2.28-2.48 (m, 1H) 2.56-2.75 (m, 1H) 3.01 (s,6H) 3.47-3.61 (m, 1H) 3.68-3.84 (m, 2H) 3.91 (dd, 1H) 4.13 (quin, 1H)7.42- 7.57 (m, 2H) 7.67 (d, 1H) 7.78- 7.95 (m, 2H) 8.09 (dd, 1H) 8.43(s, 1H) 8.62 (d, 1H). 16 Intermediate 81.3 83

LCMS (method A): [M + H]⁺ = 479.2, t_(R) = 2.21 min. ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.50-1.60 (m, 2H) 2.03 (d, 2H) 2.05 (s, 3H) 3.55 (t, 2H)3.58-3.68 (m, 2H) 3.81 (t, 1H) 3.97-4.00 (m, 2H) 4.27 (t, 2H) 7.48 (dd,1H) 7.63 (d, 1H) 7.70 (d, 1H) 7.85-7.89 (m, 2H) 8.09 (dd, 1H) 8.49-8.52(m, 2H) 17 (4 steps) Intermediates I + Q2 84

LCMS (method A): [M + H]⁺ = 435.0, t_(R) = 3.30 min. ¹H NMR (400 MHz,MeOH-d₄) δ ppm 1.46-1.64 (m, 2H) 2.03 (d, 2H) 2.18 (s, 3H) 3.52- 3.61(m, 2H) 3.61-3.72 (m, 1H) 3.99 (dt, 2H) 7.48 (dd, 1H) 7.63 (d, 1H) 7.69(d, 1H) 7.82-7.86 (m, 1H) 7.86-7.92 (m, 1H) 8.10 (dd, 1H) 8.46 (s, 1H)8.51 (d, 1H) 16 Intermediate 83.3 85

LCMS (method A): [M + H]⁺ = 510.1, t_(R)= 1.73 min. ¹H NMR (400 MHz,MeOH-d₄) δ ppm 2.15-2.30 (m, 3 H) 2.30-2.45 (m, 1 H) 2.57- 2.72 (m, 1 H)3.01 (s, 6 H) 3.48-3.59 (m, 2 H) 3.69- 3.78 (m, 1H) 3.78-3.85 (m, 3 H)3.90 (dd, J = 10.79, 7.53 Hz, 1 H) 4.13 (quin, J = 7.15 Hz, 1 H)4.21-4.36 (m, 2 H) 7.41 (d, J = 2.76 Hz, 1 H) 7.49 (dd, J = 8.78, 2.01Hz, 1 H) 7.74 (d, J = 2.01 Hz, 1 H) 7.81 (dd, J = 11.80, 1.00 Hz, 1 H)7.90 (d, J = 8.78 Hz, 1 H) 8.32 (d, J = 1.00 Hz, 1 H) 8.61 (d, J = 2.76Hz, 1 H) 18 (4 steps) Intermediates H + Q2 86

LCMS (method A): [M + H]⁺ = 478.0, t_(R) = 1.74 min. ¹H NMR (400 MHz,MeOH-d₄) δ ppm 2.18 (s, 3H) 2.37 (s, 3H) 2.65 (m, 4H) 3..36 (m, 4H) 3.79(t, 2H) 4.25 (t, 2H) 7.41 (dd, 1H) 7.46 (d, 1H) 7.74 (d, 1H) 7.83 (m,2H) 8.03 (d, 1H) 8.43 (s, 1H) 8.75 (d, 1H) 19 (3 steps) IntermediatesI + Q14

Comparative Examples

The following compounds were used for comparative purposes, andsynthesized according to the procedures described in the citedreference:

Comparator No. 1:6-{Difluoro-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-methyl}-quinoline(JNJ-38877605)

6-{Difluoro-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl]-methyl}-quinolinewas disclosed as Example 61 in WO 2007/075567.

Comparator No. 2:1-{3-[3-(4-Methyl-piperazin-1-yl)-quinolin-6-ylmethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}-ethanoneO-(2-hydroxy-ethyl)-oxime

1-{3-[3-(4-Methyl-piperazin-1-yl)-quinolin-6-ylmethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}-ethanoneO-(2-hydroxy-ethyl)-oxime was disclosed as Example 63 in WO 2011/020861.

Comparator No. 3:2-[4-(3-Quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanol(PF-04217903)

2-[4-(3-Quinolin-6-ylmethyl-3H-[1,2,3]triazolo[4,5-b]pyrazin-5-yl)-pyrazol-1-yl]-ethanolwas disclosed as Example 209 in WO 2007/132308 and in WO 2009/068955

Comparator No. 4:6-[6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-quinoline(SGX523)

6-[6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-quinolinewas disclosed as Example 4 in WO 2008/051808.

The activity of a compound according to the present invention can beassessed by the following in vitro & in vivo methods.

1. C-Met Enzyme Assay (EPK c-Met Profiling Assay)

A number of compounds of the present invention were assayed in anantibody based kinase phosphorylation assay as follows.

The EPK kinase assay for c-Met receptor tyrosine kinase was developed,using the purified recombinant GST-fusion protein, containing thecytoplasmic domain of the enzyme. GST-c-MET (969-1390) was purified byaffinity chromatography.

The kinase assay is based on the LanthaScreen™ technology. LanthaScreen™is the detection of Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) using lanthanide chelates to measure interactions betweenvarious binding partners. In a TR-FRET kinase assay, a long-lifetimelanthanide donor species is conjugated to an antibody that specificallybinds to a phosphorylated product of a kinase reaction that is labeledwith a suitable acceptor fluorophore. This antibody-mediated interactionbrings the lanthanide donor and the acceptor into proximity such thatresonance energy transfer can take place, resulting in a detectableincrease in the FRET signal.

The kinase reactions were performed in 384 well microtiter plates in atotal reaction volume of 10.05 μL. The assay plates were prepared with0.05 μL per well of test compound in the appropriate test concentration,as described under “preparation of compound dilutions”. The reactionswere started by combining 5 μL of ATP solution with 5 μL ofenzyme-substrate mix (consisting of kinase and substrate). The finalconcentrations in the kinase reactions were 25 mM Tris/HCl, 1 mM DTT,0.025% Tween20, 10 μM sodium orthovanadate, 0.25% BSA, 0.5% DMSO, 10 mMMgCl₂, 3 mM MnCl₂, 2 μM ATP, 50 nM Fluorescein-PolyEAY, and 0.3 nMenzyme. The reactions were incubated for 60 minutes at room temperatureand stopped by adding 5 μL of stop buffer (50 mM EDTA, 0.04% NP40, 20 mMTris/HCl). Subsequently 5 μL of detection mix (50 mM Tris/HCl, 2 mM DTT,0.05% Tween20, 20 μM sodium orthovanadate, 1% BSA, 1 nM Tb-PY20antibody) were added to the stopped reactions. After 45 minutesincubation in dark at room temperature, the plates were measured in aPerkinelmer Envision fluorescence reader. The effect of compound on theenzymatic activity was in all assays obtained from the linear progresscurves and determined from one reading (end point measurement).

Results are summarized in the Table 1-A below. “Active” compounds of theinvention have an IC₅₀ in this enzyme assay of less than 500 nM,preferably less than 100 nM, more preferably less than 50 nM and mostpreferably less than 10 nM.

As it can be seen, each of the exemplified compounds of the inventionhas an IC₅₀ value in this enzyme assay below 500 nM. The preferredcompounds of the invention each have an IC₅₀ value in this enzyme assaybelow 100 nM, and the most preferred compounds have IC₅₀ values in thisenzyme assay below 10 nM.

Results for some further compounds as described herein are summarized inthe Table 1-B below.

For comparison, results for reference examples and for comparatorcompounds are summarized below in Table 1-C.

TABLE 1-A c-Met Inhibitory activity of compounds of the invention c-MetBiochem c-Met Biochem Example No. IC₅₀ [nM] Example No. IC₅₀ [nM] 1 9 401 2 5 41 15 3 2 42 4 6 8 43 2 9 7 44 1 10 3 45 399 12 4 46 18 13 1 47 514 2 48 5 17 3 49 3 18 48 50 4 19 8 57 2 20 15 58 3 21 2 59 3 24 2 60 426 69 61 4 27 3 67 1 28 78 69 3 29 4 70 3 30 2 72 12 31 3 74 4 32 12 7524 33 4 76 7 34 45 77 5 35 4 78 2 35A 5 79 83 35B 4 80 33 36 4 81 6 37 282 6 38 2 85 15 39 23 86 10

TABLE 1-B c-Met Inhibitory activity of selected further compounds of theinvention c-Met Biochem c-Met Biochem Example No. IC₅₀ [nM] Example No.IC₅₀ [nM] 4 11 53 1 5 6 54 8 7 3 55 1.3 8 1 56 13 11 4 62 6 15 4 64 8 2219 68 5 23 11 71 6 25 4 83 8 51 4 84 8 52 2

TABLE 1-C c-Met Inhibitory activity of reference and comparatorcompounds c-Met Biochem Compound No. IC₅₀ [nM] Reference Example No. 16312 Reference Example No. 63 3 Reference Example No. 65 18 ReferenceExample No. 66 3 Reference Example No. 73 5 Comparator No. 1(JNJ-38877605) 3 Comparator No. 2 6 Comparator No. 3 (PF-04217903) 4Comparator No. 4 (SGX523) <102. GTL16 Cell Viability Assay:

GTL16 cell line is derived from a gastric cancer patient. GTL16expresses high level of c-Met receptor tyrosine kinase due to the geneamplification. The growth of GTL16 is highly dependent on c-Met kinaseactivity; hence it is used as a cell-based assay to monitor the cellularactivity of the c-Met kinase inhibitors.

GTL16 cells were seeded in DMEM medium with 10% FBS and 1% Pene. &Strep. at 5000 cells/well/90 μL in 96 well plate and incubated overnightfor attachment at 37° C. in 5% CO₂ incubator. 10-fold serials dilutionsof compounds were added to the cell as 10 μL/well. The final assayvolume was 100 μl/well. The assay plates were incubated at 37° C. in 5%CO₂ incubator for 24 hours. The viability of cells was measured usingthe CellTiter Glo (Cat#G7573 Promega) according to the protocolsuggested by the vender. Briefly, the plates were cooled at roomtemperature for 10 mins and 100 μl of CellTiter Glo reagent was addedinto each well. Plates were shaken for 10 mins. The chemiluminescentlight unit was read in Envision from Perkin Elmer. All the tests wererun at triplicates. The IC₅₀ was calculated using Spotfire software.

Results are summarized in the Table 2-A below. “Active” compounds of theinvention have an IC₅₀ in this enzyme assay of less than 1500 nM,preferably less than 1000 nM, preferably less than 500 nM, morepreferably less than 100 nM, more preferably less than 20 nM and mostpreferably less than 10 nM.

Each of the exemplified compounds has an IC₅₀ value in this enzyme assaybelow 1500 nM. The preferred compounds of the invention each have anIC₅₀ value in this enzyme assay below 500 nM, more preferred compoundshave IC₅₀ values in this enzyme assay below 100 nM and the mostpreferred compounds have IC₅₀ values in this enzyme assay below 10 nM.

Results for some further compounds as described herein are summarized inthe Table 2-B below.

For comparison, results for reference examples and for comparatorcompounds are summarized below in Table 2-C.

TABLE 2-A c-Met inhibitory activity of selected compounds of theinvention Example GTL-16 Proliferation Example GTL-16 Proliferation No.IC₅₀ [nM] No. IC₅₀ [nM] 1 2 39 9 2 6 40 1 3 1 41 6 6 27 42 0.6 9 3 430.3 10 21 44 0.8 12 0.6 47 3 13 0.4 48 1 14 2 49 4 17 3 50 1 18 105 5710 19 35 58 8 20 1 59 11 21 36 60 11 24 0.9 61 2 26 10 67 0.3 27 4 69 328 2 70 1 29 40 72 86 30 2 74 2 31 0.4 75 10 32 4 76 54 33 4 77 8 34 178 3 35 0.4 79 1138 35A 1 80 125 35B 4 81 4 36 0.9 82 4 37 0.9 85 23 383 86 51

TABLE 2-B c-Met inhibitory activity of selected further compounds of theinvention GTL-16 Proliferation GTL-16 Proliferation Example No. IC₅₀[nM] Example No. IC₅₀ [nM] 4 1 53 17 5 385 54 14 7 24 55 1 8 1 56 33 112 62 73 15 2 64 5 22 2 68 3 23 289 71 35 25 8 83 1 51 9 84 3 52 2

TABLE 2-C c-Met Inhibitory activity of reference and comparatorcompounds GTL-16 Proliferation Compound No. IC₅₀ [nM] Reference ExampleNo. 16 1182 Reference Example No. 63 8 Reference Example No. 65 10Reference Example No. 66 3 Comparator No. 1 (JNJ-38877605) <10Comparator No. 3 (PF-04217903) <103. hPDE3 Assay

Phosphodiesterase-3 (PDE3) is one of a family of phosphodiesterasesresponsible for the regulation of cyclic nucleotide second messengers.Human PDE3 has high affinity for both cAMP and cGMP and is distributedin a wide range of tissues and cell types. Inhibitors of hPDE3 arepotentially useful as inotropic/vasodilator, antithrombotic andanti-inflammatory agents (Komas et al. 1996). Agents that inhibit PDE3were originally investigated for the treatment of heart failure but haveunwanted arrhythmic side effects (Dart R. C., Medical Toxicology,Edition 3, page 708; Lippincott 2004).

PDE3 assays to measure the inhibitory potential of compounds at thisenzyme are well known to the person skilled in the art. For example,cAMP and cGMP levels can be measured by the use of the tritiumcontaining compounds ³HcAMP and ³HcGMP as described in [Hansen, R. S.,and Beavo, J. A., PNAS 1982; 79: 2788-92]. To screen a compound poolcomprised of a large number of compounds, the microtiter plate-basedscintillation proximity assay (SPA) as described in [Bardelle, C. et al.(1999) Anal. Biochem. 275: 148-155] can be applied. Alternatively, thephosphodiesterase activity of the recombinant protein can be assayedusing a commercially available SPA kit (Amersham Pharmacia). Such anassay for PDE3 was e.g. described within Kima et al (2004) Bioorganic &Medicinal Chemistry Letters, Vol 14(9): 2099-2103. An alternative PDE3assay for measuring the PDE3 inhibitory potential of c-Met inhibitorswas disclosed in WO 2010/138673.

A possible isolation method for human PDE3 from human platelets isdisclosed within Ito et al (1996) Cell Signal. 1996 December;8(8):575-81.

Here, compounds of formula I were screened for their ability to inhibithuman PDE3 in the assay based on Amersham Pharmacia Biotech'sPhosphodiesterase (PDE) [³H]-adenosine 3′,5′ cyclic phosphate ([³H]cAMP)Scintillation Proximity Assay (SPA). The assay is based on thehydrolysis of [³H]cAMP, by human platelet PDE3, to [³H]5′-adenosidemonophosphate (5′-AMP). The [³H]5′-AMP is specifically captured byyttrium silicate SPA beads in the presence of zinc sulphate. When[³H]5′-AMP binds to the beads, β-particles are emitted and excite, bytheir proximity, the fluorophore in the beads and hence produce light.Free [³H]cAMP in turn does not activate the scintillant, since theunbound radioactivity is released too distant from the scintillant, andhence does not produce light.

Materials

-   -   Optiplate and TopSeal-S (Can berra Packard)    -   Human platelet PDE3 (partially purified from human platelets)—a        titration curve of human platelet PDE3 activity was performed to        optimise the concentration of hPDE3 required in the assay.    -   Yttrium silicate SPA beads and [³H]cAMP (Amersham)    -   Tris-Base, magnesium chloride, ethylenediaminetetraacetic acid        (di-sodium salt), bovine serum albumin BSA and cAMP (Sigma)        Solutions and Buffers:    -   Assay buffer: 7.56 g Tris-Base was dissolved in approximately        800 mL distilled water and the pH adjusted to 7.5 with 1 M        hydrochloric acid. 10.3 mL 1 M magnesium chloride and 4.25 mL        0.5 M EDTA were added. The solution was made to 1 L with        distilled water and stored at 4° C. On day of use 18 mL of the        above solution was removed and 2 mL 5 mg/ml BSA were added        thereto.    -   Enzyme buffer: 10 mM Tris-HCl at pH 7.5, 1 mM EDTA    -   Yttrium silicate SPA beads: 1 vial was reconstituted in 28 mL        distilled water and stored at 4° C.        Assay

The assay was performed in a final volume of 100 μL per well of anOptiplate (Canberra Packard). A 10 μL aliquot of the test compounddissolved in DMSO/distilled water was placed in a well of an Optiplateplate, followed by the addition of 80 μL ‘Assay mix’ (5.5 μL [³H]cAMPand 88 μL “cold” cAMP were diluted to 8.8 mL using assay buffer). Thereaction was started by adding 10 μL hPDE3 (50 μL stock hPDE3 solutionwas diluted 50 fold to 2.5 mL using enzyme buffer). The plate wasincubated at room temperature for 30 min, the reaction was thenterminated by the addition of 50 μL Yttrium silicate SPA beads(pre-warmed to room temperature) to all wells. The plate incubated atroom temperature for at least 15 min. The plate was sealed usingTopSeal-S according to the manufacturer's instructions and counted usinga Packard TopCount, each well being counted for 1 min. IC₅₀ values weredetermined using non-linear regression.

Results of some exemplary compounds are summarized in the Table 3-Abelow. Compounds of the invention have preferably high IC₅₀ values inthis enzyme assay, preferably more than 5 μM, more preferably more than10 μM and most preferably more than 30 μM. As it can be seen, each ofthe exemplified compounds has an IC₅₀ value in this enzyme assay above10 μM. Results for some further compounds as described herein aresummarized in the Table 3-B below.

For comparison, results for reference examples and for comparatorcompounds are summarized below in Table 3-C. As it can be seen from thedata comparator compounds with different core structures showsignificantly lower PDE3 IC₅₀ values.

TABLE 3-A PDE3 Inhibitory activity of selected compounds of theinvention Example No. hPDE3 IC₅₀ [μM] Example No. hPDE3 IC₅₀ [μM] 3 1457 10 6 30 58 13 10 17 59 6 13 24 61 12 21 30 69 >30 27 17 70 >30 30 2574 18 31 30 76 14 32 26 77 12 34 30 78 28 35A 16 79 >30 42 29 80 30 4320 82 11 46 30 85 30 47 12 86 27 50 30

TABLE 3-B PDE3 Inhibitory activity of selected further compounds of theinvention Example No. hPDE3 IC₅₀ [μM] 8 30 15 30 22 15 23 30 51 7 53 1454 13 55 >30 56 17 62 18 68 10 83 20 84 6

TABLE 3-C PDE3 Inhibitory activity of reference and comparator compoundsc-Met Biochem Compound No. IC₅₀ [nM] Reference Example No. 63 15Reference Example No. 66 >30 Reference Example No. 73 7 Comparator No. 1(JNJ-38877605) 4 Comparator No. 2 4 Comparator No. 3 (PF-04217903) 7Comparator No. 4 (SGX523) 34. Metabolic Stability in Monkey Liver Cytosol Fractions

The compounds of the invention were analysed with regard to theirmetabolic stability in view of the recent publication of apparentspecies dependent toxicity reported for6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinoline(SGX523), a c-MET inhibitor that entered clinical development for thetreatment of solid tumors [Diamond et al (2010) DRUG METABOLISM ANDDISPOSITION, Vol. 38, No. 8, 1277-1285]. Patients treated with SGX523exhibited compromised renal function presumably resulting from crystaldeposits in renal tubules. Metabolite profiling of SGX523 indicated thatmetabolite[6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylthio)quinolin-2(1H)-one(M11)] was generated by monkey and human liver S-9, and to a lesserextent by rat S-9, whereas M11 was absent in dog S-9 incubations. It wasshown that aldehyde oxidase (AO) was responsible for the generation ofthe 2-quinolinone-SGX523 metabolite which is markedly less-soluble thanSGX523 itself. It was concluded that this metabolite is likely involvedin the observed obstructive nephropathy reported in clinical studies,and that there is a need to conduct thorough metabolic evaluations earlyin drug development to select the most relevant nonclinical species fortoxicological evaluation.

The metabolic stability of the compounds of the invention with regard tohuman aldehyde oxidase (AO) was analysed by using monkey liver cytosolwhich also has a high level of AO and is most comparable to the humansituation [Pryde et al (2010) “Aldehyde Oxidase: An Enzyme of EmergingImportance in Drug Discovery” J. Med. Chem. 53, 8441-8460].

Incubation Protocol

Test compound was dissolved in DMSO to 10 mM, diluted to 10 μM with 0.6%ACN in H₂O (1000-fold). The 10-μM solution was further diluted in to 2μM with H₂O. In a 400-uL reaction system, the final concentration fortest compound and cytosol is 1 μM and 2 mg/ml, respectively. Monkeyliver cytosol is pooled monkey liver cytosol (male cyno), 20 mg/ml [fromiPhase Pharma Service (Beijing, China) Catalogue#6CMCC1, Lot#6MCMCC001].The volumes added to the reaction mixture were as follows:

Reagent Final concentration Stock 400 uL Potassium Phosphate 50 mM 500mM  40 uL buffer (pH 7.4) Monkey liver cytosol 2 mg/ml 20 mg/ml  40 uLTest compound 1 μM 2 μM 200 uL H₂O 120 uL

There was a 10 min preincubation at 37° C., and then the reactions areinitiated by addition of test compound. At specific reaction time points(30, 60 and 120 minutes), reaction aliquots (25 μL) are removed andreactions are terminated by addition of acetonitrile (100 μL) containinginternal standard (125 ng/ml JNJ-38877605). For time 0 point, thecytosol fraction was first terminated by the addition of acetonitrile,followed by the addition of substrate. All the samples were centrifugedat ˜3400×g at 4° C. for 10 min. The supernatants were diluted 1:1 (v/v)in H₂O and analyzed by LC-MS/MS.

In Vitro Clearance Calculation

Each microsomal elimination rate, k_(mic), is based on a 4-pointelimination curve tested in singlet. LC-MS/MS raw data for a reactionplate is returned as integrated analyte peak areas for the TA and IS.These values may be converted to analyte: IS peak area ratios tostandardize data comparisons. The reaction time point (eg. 0, 30, 60,120 min) is plotted versus the natural logarithm of percent TA remainingrelative to 0 minutes (based on relative peak area ratio). The slope ofthis clearance plot, k_(mic), is used to calculate the in vitrohalf-life,

$t_{1\text{/}2} = {\frac{0.693}{- k_{mic}}.}$

In order to focus on linear reaction kinetics, whenever possible, datapoints representing <10% TA remaining are generally excluded from thedefinition of the clearance plot slope. The reaction t_(1/2) is the coreexperimental value used for calculating in vitro intrinsic clearancevalue, CL_(int) (μL/min/mg microsomal protein),

${CL}_{int} = {\frac{0.693}{t_{1\text{/}2}} \cdot {\frac{V}{M}.}}$

Here, V is the incubation volume (μL), and M is the microsomal proteincontent in the incubation (mg).

Results

Results of some exemplary compounds are summarized in the Table 4-Abelow. Compounds of the invention have preferably a high in vitrohalf-life t_(1/2) in this assay, preferably a t_(1/2) of more than 250min, more preferably more than 500 min and more than 1000 min, and mostpreferably more than 5000 min or even higher.

As it can be seen, each of the exemplified compounds demonstrates goodmetabolic stability in this assay. Preferred compounds of the inventionare metabolically stable, and/or produce metabolites that do not haveundesirable effects in the body. For example the metabolites formed donot interfere, or have limited interference, with normal renal function.

Results for some further compounds as described herein are summarized inthe Table 4-B below.

For comparison, results for reference examples and for comparatorcompounds are summarized below in Table 4-C.

As it can be seen from the table especially compounds with nosubstituent in the 3-position of the quinoline ring show low metabolicstability in this assay.

TABLE 4-A Metabolic stability of selected compounds of the inventionExample No. t_(1/2) [min] Example No. t_(1/2) [min] 2 1879 59 642 3 44761 838 6 19143 69 19143 10 3093 70 3656 13 350 72 1141 17 606 74 4527 21500 75 34931 27 7002 76 1698 29 608 77 9999 33 891 78 2334 37 653 806352 40 11628 82 2019 43 882 85 917 47 540 86 3544 50 1856

TABLE 4-B Metabolic stability of further selected compounds of theinvention Example No. t_(1/2) [min] Example No. t_(1/2) [min] 5 1347 515 7 351 52 6 8 1106 62 8404 11 144 64 3 15 414 68 271 23 1498 83 228 25185 84 207

TABLE 4-C Metabolic stability of reference and comparator compoundsCompound No. t_(1/2) [min] Reference Example No. 66 407 Comparator No. 2542 Comparator No. 4 (SGX523) 284

Furthermore, certain preferred compounds of the invention have goodexposure in vivo, and/or have a favourable solubility profile. Assays tomeasure bioavailability, pharmacokinetic profiles and solubility arewell known in the art.

Certain preferred compounds of the invention produce metabolites in vivowhich themselves have a favourable solubility profile, thereby avoidingor limiting undesirable effects in vivo.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the following claims.

We claim:
 1. A compound of formula (I)

wherein R¹ is selected from (i) pyrazolyl, optionally substituted by(C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionally substituted by one OHgroup, and (ii) —CR⁹═N—O—R¹⁰, wherein R⁹ is hydrogen or (C₁-C₄)alkyl;and, R¹⁰ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionallysubstituted by one OH group; R² is selected from hydrogen and halo; andR³ is —(C₀-C₂)alkyl-heterocyclyl¹, wherein heterocyclyl¹ is a 4, 5, 6, 7or 8 membered saturated or partially unsaturated N-heterocyclic ringwhich is attached via the N-atom and optionally comprises additional 1or 2 ring heteroatoms independently selected from N, O and S in aposition or positions other than adjacent to the linking N atom, whereinthe total number of ring S-atoms does not exceed 1, and the total numberof ring O-atoms does not exceed 1, wherein the N-heterocyclic ring isoptionally substituted (i) by one, two or three substituentsindependently selected from —OH, halo, —CONH₂, —CONH(C₁-C₄)alkyl,—CON((C₁-C₄)alkyl)₂, —COO(C₁-C₄)alkyl, —NH₂, —NH—COO(C₁-C₄)alkyl,—NH(C₁-C₃)alkyl, —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl²,—(C₃-C₈)cycloalkyl, phenyl and (C₁-C₄)alkyl, said (C₁-C₄)alkyl beingoptionally substituted by one, two or three substituents independentlyselected from OH and halo; wherein heterocyclyl² is a 5 or 6-memberedsaturated or partially unsaturated monocyclic group comprising 1 or 2ring heteroatoms independently selected from N and O, wherein the totalnumber of ring O atoms does not exceed 1, and which is optionallysubstituted by one or two substituents independently selected from OHand (C₁-C₄)alkyl; or (ii) by two groups which are attached to the samecarbon atom and are combined into a cyclic 4, 5, 6, or 7 memberedsaturated or partially unsaturated ring system optionally comprising 1or 2 ring heteroatoms independently selected from N, O and S, whereinthe total number of ring S atoms does not exceed 1, which cyclic ringsystem is optionally substituted by —OH or (C₁-C₄)alkyl; and wherein thesubstituted N-heterocyclic ring is optionally substituted by one or twoadditional (C₁-C₄)alkyl groups; or a pharmaceutically acceptable saltthereof.
 2. A compound or pharmaceutically acceptable salt thereofaccording to claim 1, wherein R³ is selected from (i) optionallysubstituted —(C₁-C₂)alkyl-heterocyclyl¹, under the proviso that R¹ isoptionally substituted pyrazole, and (ii) optionally substitutedheterocyclyl¹.
 3. A compound or pharmaceutically acceptable salt thereofaccording to claim 1, wherein R¹ is pyrazolyl, optionally substituted by(C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionally substituted by one OHgroup.
 4. A compound or pharmaceutically acceptable salt thereofaccording to claim 1, wherein R¹ is —CR⁹═N—O—R¹⁰, wherein R⁹ is hydrogenor (C₁-C₄)alkyl; and, R¹⁰ is hydrogen or (C₁-C₄)alkyl, said (C₁-C₄)alkylbeing optionally substituted by one OH group; and R³ is optionallysubstituted heterocyclyl¹.
 5. A compound or pharmaceutically acceptablesalt thereof according to claim 4, wherein R¹ is —CR⁹═N—O—R¹⁰, whereinR⁹ is (C₁-C₂)alkyl; and, R¹⁰ is hydrogen or (C₁-C₂)alkyl, said(C₁-C₂)alkyl being optionally substituted by one OH group.
 6. A compoundor pharmaceutically acceptable salt thereof according to claim 2,wherein R³ is -methyl-heterocyclyl¹, wherein heterocyclyl¹ is a 5 or 6membered saturated N-heterocyclic ring which is attached via the N-atomand optionally comprises one additional ring heteroatom selected from Nand O in a position other than adjacent to the linking N atom, whereinany additional ring N-atom is substituted with an (C₁-C₄)alkyl group. 7.A compound or pharmaceutically acceptable salt thereof according toclaim 1, wherein R³ is heterocyclyl¹, wherein heterocyclyl¹ is a 4, 5,6, or 7 membered saturated N-heterocyclic ring which is attached via theN-atom and optionally comprises one additional ring heteroatomindependently selected from N and O in a position other than adjacent tothe linking N atom, wherein the N-heterocyclic ring is optionallysubstituted (i) at one or two ring C-atoms by overall one or twosubstituents independently selected from —OH, halo, —NH₂,—NH—COO(C₁-C₄)alkyl, —NH(C₁-C₃)alkyl, —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl,heterocyclyl², and (C₁-C₄)alkyl; wherein heterocyclyl² is a 5 or6-membered saturated N-heterocyclic² ring which is attached via theN-atom; (ii) at the optionally present additional ring N-atom by onesubstituent selected from —COO(C₁-C₄)alkyl, —(C₅-C₆)cycloalkyl, phenyland (C₁-C₄)alkyl, said (C₁-C₄)alkyl being optionally substituted by one,two or three substituents independently selected from OH and halo; or(iii) by two groups which are attached to the same carbon atom and arecombined into a cyclic 4, 5, or 6 membered saturated ring systemcomprising 1 ring O-atom.
 8. A compound or pharmaceutically acceptablesalt thereof according to claim 7, wherein R³ is heterocyclyl¹, whereinheterocyclyl¹ is a 4, 5, 6, or 7 membered saturated N-heterocyclic ringwhich is attached via the N-atom and optionally comprises one additionalring heteroatom independently selected from N and O in a position otherthan adjacent to the linking N atom, wherein the N-heterocyclic ring isoptionally substituted (i) at one or two ring C-atoms by overall one ortwo substituents independently selected from —OH, halo, —NH₂,—NH(C₁-C₃)alkyl, —N((C₁-C₃)alkyl)₂, —O(C₁-C₄)alkyl, heterocyclyl², and(C₁-C₄)alkyl; wherein heterocyclyl² is a 5 or 6-membered saturatedN-heterocyclic² ring which is attached via the N-atom; (ii) at theoptionally present additional ring N-atom by one substituent selectedfrom —(C₅-C₆)cycloalkyl, phenyl and (C₁-C₂)alkyl, said (C₁-C₂)alkylbeing optionally substituted by one, two or three substituentsindependently selected from OH and halo; or (iii) by two groups whichare attached to the same carbon atom and are combined into a cyclic 4 or6 membered saturated ring system comprising 1 ring O-atom.
 9. A compoundor pharmaceutically acceptable salt thereof according to claim 1,wherein R¹ is selected from 1-methyl-1H-pyrazol-4-yl, 1-yl-ethanoneoxime, and 1-yl ethanone O-(2-hydroxyethyl)-oxime, R² is hydrogen orfluoro, R³ is heterocyclyl¹, wherein heterocyclyl¹ is selected from a) a4, 5 or 6 membered saturated N-heterocyclic ring attached via the N-atomand substituted (i) at one or two ring C-atom or atoms by overall one ortwo substituents selected from —OH, fluoro, —NH₂, —N(methyl)₂, methoxy,piperidin-1-yl, pyrrolidin-1-yl, and methyl; or (ii) by two groups whichare attached to the same carbon atom and are combined into a cyclic 4 or6 membered saturated ring system comprising 1 ring O-atom; b) a 6membered saturated N-heterocyclic ring attached via the N-atom andcomprising one ring O-atom in a position other than adjacent to thelinking N atom, wherein the N-heterocyclic ring is optionallysubstituted by one or two methyl groups; and c) a 6 or 7 memberedsaturated N-heterocyclic ring attached via the N-atom and comprising oneadditional ring N-atom in a position other than adjacent to the linkingN atom, wherein the N-heterocyclic ring is optionally substituted (i) atthe additional ring N-atom a substituent selected from cyclohexyl,phenyl and (C₁-C₂)alkyl, said (C₁-C₂)alkyl being optionally substitutedby one, two or three substituents independently selected from OH andhalo; or (ii) at one or two ring C-atoms by one or two methyl groups.10. A compound or pharmaceutically acceptable salt thereof according toclaim 1, wherein R¹ is selected from 1-methyl-1H-pyrazol-4-yl,1-yl-ethanone oxime, and 1-yl ethanone O-(2-hydroxyethyl)-oxime, R² ishydrogen or fluoro, R³ is heterocyclyl¹, wherein heterocyclyl¹ isselected from piperazin-1-yl, morpholin-4-yl, 4-methoxypiperidin-1-yl,4-hydroxypiperidin-1-yl, 3,5-dimethylpiperazin-1-yl,3-N,N-dimethylaminopyrrolidin-1-yl, 3-amino-piperidin-1-yl,3-amino-pyrrolidin-1-yl and 4-methyl-piperazin-1-yl.
 11. A compound orpharmaceutically acceptable salt thereof according to claim 10, whereinR¹ is selected from 1-methyl-1H-pyrazol-4-yl, R² is hydrogen or fluoro,and R³ is heterocyclyl¹, wherein heterocyclyl¹ is selected frompiperazin-1-yl, morpholin-4-yl, 4-methoxypiperidin-1-yl,4-hydroxypiperidin-1-yl, 3,5-dimethylpiperazin-1-yl, and4-methyl-piperazin-1-yl.
 12. A compound or pharmaceutically acceptablesalt thereof according to claim 1, wherein R² is selected from hydrogenand fluoro, preferably hydrogen.
 13. A compound or pharmaceuticallyacceptable salt thereof according to claim 1, wherein the compound isselected from No. 21-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-amineNo. 3(S)—N,N-Dimethyl-1-(6-(6-(1-methyl-1H-pyrazol-3-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)pyrrolidin-3-amineNo. 66-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-((4-methylpiperazin-1-yl)methyl)quinolineNo. 101-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-3-amineNo. 126-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2-oxa-6-azaspiro[3.3]heptaneNo. 13(S)-1-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-N,N-dimethylpyrrolidin-3-amineNo. 146-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)quinolineNo. 173-(4-Methyl-1,4-diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolineNo. 193-(1,4-Diazepan-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolineNo. 211-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)piperidin-4-amineNo. 246-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-3-(4-methyl-piperazin-1-yl)-quinolineNo. 276-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(piperazin-1-yl)quinolineNo. 286-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)quinolineNo. 292-(4-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-1,4-diazepan-1-yl)ethanolNo. 303-(1,4′-Bipiperidin-1′-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolineNo. 313-(1,4′-Bipiperidin-1′-yl)-6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolineNo. 323-(4-Cyclohexylpiperazin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolineNo. 336-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-(pyrrolidin-1-yl)piperidin-1-yl)quinolineNo. 346-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-phenylpiperazin-1-yl)quinolineNo. 352-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholineNo. 35A(S)-2-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholineNo. 35B(R)-2-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholineNo. 364-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2-methylmorpholineNo. 372,6-Dimethyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholineNo. 384-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-2,6-dimethylmorpholine No. 403-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-6-(8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolineNo. 423-((3S,5R)-3,5-Dimethylpiperazin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolineNo. 433-(4-Methoxypiperidin-1-yl)-6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolineNo. 446-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(4-methoxypiperidin-1-yl)quinolineNo. 46(S)-6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(2-methylpiperazin-1-yl)quinolineNo. 472-(6-((6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)-8-oxa-2-azaspiro[4.5]decaneNo. 482-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-8-oxa-2-azaspiro[4.5]decaneNo. 491-(6-((6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-olNo. 501-(6-((8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)thio)quinolin-3-yl)piperidin-4-olNo. 574-(6-(6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholineNo. 584-(6-(8-Fluoro-6-(1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholineNo. 593-Methyl-4-(6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-morpholineNo. 604-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)-3-methylmorpholineNo. 613-(4,4-Difluoro-piperidin-1-yl)-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolineNo. 673-(4,4-Difluoro-piperidin-1-yl)-6-[8-fluoro-6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolineNo. 694-(6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholineNo. 704-(6-(8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)morpholineNo. 722-(4-(3-(3-Morpholin-4-yl-quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-1H-pyrazol-1-yl)ethanolNo. 743-(4-Methyl-piperazin-1-yl)-6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolineNo. 754-((6-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)quinolin-3-yl)methyl)-morpholineNo. 76(E)-1-(3-((3-(4-Hydroxypiperidin-1-yl)quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-ethanoneO-(2-hydroxyethyl)oxime No. 77(E)-1-(3-((3-Morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneoxime No. 78(E)-1-(3-((3-Morpholin-4-yl-quinolin-6-yl)thio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-(2-hydroxyethyl)oxime No. 81(S,E)-1-(3-(3-(3-(Dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-2-hydroxyethyl oxime No. 82(S,E)-1-(3-(3-(3-(Dimethylamino)pyrrolidin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneoxime No. 85(S,E)-1-{3-[3-(3-Dimethylamino-pyrrolidin-1-yl)-quinolin-6-ylthio]-8-fluoro-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-(2-hydroxy-ethyl)-oxime, and No. 86(S,E)-1-(3-(3-(4-Methylpiperazin-1-yl)quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethanoneO-2-hydroxyethyl oxime.
 14. A compound or pharmaceutically acceptablesalt thereof, wherein the compound is selected from No. 8{6-[8-Fluoro-6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-(1-methyl-piperidin-4-yl)-amine,and No. 15(1-Methyl-piperidin-4-yl)-{6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylsulfanyl]-quinolin-3-yl}-amine.15. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound or a pharmaceutically acceptable salt thereofaccording to claim 1, and one or more pharmaceutically acceptablecarriers.